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Abstract:

This invention relates to a novel class of hybrid lipid compound based on
pentaerythritol, their intermediates, preparation methods and uses
thereof. Different kinds of functional groups such as alkyl chain,
siloxane group, azobenzene, porphyrins, cholesterol, benzene ring and
carboxyl were introduced into the four hydroxyl groups of pentaerythritol
through chemical reaction to obtain the final hybrid lipid compounds
based on pentaerythritol. Cerasomes prepared from such lipids have
uniform size, silicate network surface, good stability and
biocompatibility, and the leakage of drugs is not easy. The present
liposome can be used as functional materials such as drugs or drug
carriers, or used for optical storage and molecular devices, simulation,
design and synthesis of artificial systems, nano-composite membrane
materials and the removal of organic pollutants, etc., in addition, the
preparation method of the present invention is simple, and it is easy for
industrial production.

Claims:

1-51. (canceled)

52. A hybrid lipid compound based on pentaerythritol with a
constructional formula ##STR00208## wherein: R1 is
C.sub.6.about.C18 alkyl; R2 is C.sub.6.about.C18 alkyl;
R5 is one among the group consisting of
--CO(CH2)5N(CH3)2(CH2)3Si(X)3Y,
--CO(CH2)2CONH(CH2)3Si(X)3,
--CO(CH2)3CONH(CH2)3Si(X)3 and
--CONH(CH2)3Si(X)3, in which X is ethoxy or methoxy, Y is
halogen group; and a is 2 or 3.

53. A hybrid lipid compound based on pentaerythritol with a
constructional formula ##STR00209## wherein: R1 is
C.sub.6.about.C18 alkyl; R2 is C.sub.6.about.C18 alkyl;
R3 is one among the group consisting of
--CO(CH2)2CONH(CH2)3Si(X)3,
--CO(CH2)3CONH(CH2)3Si(X)3 and
--CONH(CH2)3Si(X)3, in which X is ethoxy or methoxy; a is
2 or 3; X1 is one among the group consisting of --H,
--CH.sub.3.quadrature. CH3O--, halogenated group and --NO2;
Y1 is one among the group --H, --CH3, CH3O-- and
halogenated group.

54. The hybrid lipid compound of claim 53, wherein when Y1 is
attached at the 2-position to the azobenzene unit, Y1 is --H or
halogenated group; when Y1 is attached at the 3-position of the
azobenzene unit, Y1 is one among the group consisting of --H,
--CH3 and CH3O--.

55. A hybrid lipid compound based on pentaerythritol with a
constructional formula ##STR00210## wherein: R1 is
C.sub.6.about.C18 alkyl; R2 is C.sub.6.about.C18 alkyl;
R3 is one among the group consisting of
--CO(CH2)2CONH(CH2)3Si(X)3,
--CO(CH2)3CONH(CH2)3Si(X)3 and
--CONH(CH2)3Si(X)3, in which X is ethoxy or methoxy; and a
is 2 or 3.

56. A hybrid lipid compound based on pentaerythritol with a
constructional formula ##STR00211## wherein: R1 is
C.sub.6.about.C18 alkyl; R2 is C.sub.6.about.C18 alkyl;
R3 is one among the group consisting of
--CO(CH2)2CONH(CH2)3Si(X)3,
--CO(CH2)3CONH(CH2)3Si(X)3 and
--CONH(CH2)3Si(X)3, in which X is ethoxy or methoxy; a is
2 or 3; X2 is one among the group consisting of --H, --CH3,
CH3O-- and halogenated group; M is the metal ion coordinated with
porphyrin ring which is one among the group consisting of Iron, Zinc,
Magnesium, Manganese, Cobalt, Copper, Molybdenum, Chromium, Gadolinium,
Nickel, Vanadium, Aluminum, Gallium and Iridium.

57. A hybrid lipid based on pentaerythritol with a constructional formula
##STR00212## wherein: R1 is C.sub.6.about.C18 alkyl; R2
is C.sub.6.about.C18 alkyl; R3 is one among the group
consisting of --CO(CH2)2CONH(CH2)3Si(X)3,
--CO(CH2)3CONH(CH2)3Si(X)3 and
--CONH(CH2)3Si(X)3, in which X is ethoxy or methoxy; a is
2 or 3; X1 is one among the group consisting of --H, --CH3,
CH3O--, halogenated group and --NO.sub.2.

58. A hybrid lipid compound based on pentaerythritol with a
constructional formula ##STR00213## wherein: R4 is
C.sub.6.about.C18 alkyl; R5 is one among the group consisting
of --CO(CH2)5N(CH3)2(CH2)3Si(X)3Y,
--CO(CH2)2CONH(CH2)3Si(X)3,
--CO(CH2)3CONH(CH2)3Si(X)3 and
--CONH(CH2)3Si(X)3, in which X is ethoxy or methoxy and Y
is halogenated group.

59. A hybrid lipid compound based on pentaerythritol with a
constructional formula ##STR00214## wherein: R1 is
C.sub.6.about.C18 alkyl; R2 is C.sub.6.about.C18 alkyl,
R8 is one among the group consisting of
CO(CH2)2CONH(CH2)3Si(X)3,
--CO(CH2)3CONH(CH2)3Si(X)3 and
--CONH(CH2)3Si(X)3, in which X is ethoxy or methoxy;
R9 is --CO(CH2)2COOH or --CO(CH2)3COOH; and a is
2 or 3.

60. A method for making the hybrid lipid compound of claim 52 comprises
following steps: 1) forming a compound 1 with a constructional formula
##STR00215## by reacting alkyl amines and alkyl bromide under heating
reflux through substitution reaction, wherein the alkyl amines is
R1--NH2 and the alkyl bromide is R2--Br, in which R1
is C.sub.6.quadrature.C18 alkyl and R2 is
C.sub.6.quadrature.C18alkyl; 2) forming a compound 2 with a
constructional formula ##STR00216## by reacting the compound 1 with
succinic anhydride or glutaric anhydride through nucleophilic reaction,
wherein a is 2 or 3; then forming a compound 3 with a constructional
formula ##STR00217## by reacting the compound 2 with excess 4 to 6
times of pentaerythritol through esterification reaction, wherein a is 2
or 3; 3) forming a hybrid lipid compound with a constructional formula
##STR00218## by reacting the compound 3 with
3-isocyanatopropyltriethoxysilane or 3-isocyanatopropyltrimethoxysilane
through nucleophilic reaction, wherein R51
CONH(CH2)3Si(X)3, in which X is ethoxy or methoxy; or
forming a hybrid lipid with a constructional formula ##STR00219## by
reacting the compound 3 with 6-Bromohexanoyl chloride through
esterification reaction, following reacting with dimethylamine gas
saturated tetrahydrofuran solution through nucleophilic reaction, and
then reacting with 3-Bromopropyltriethoxysilane or
3-Bromopropyltrimethoxysilane through nucleophilic reaction, wherein
R52 is
--CO(CH2)5N(CH3)2(CH2)3Si(X)3Y, in
which X is ethoxy or methoxy and Y is halogenated group; or forming a
hybrid lipid compound with a constructional formula ##STR00220## by
reacting the compound 3 with succinic anhydride or glutaric anhydride
through nucleophilic reaction, following reacting with
3-aminopropyltriethoxysilane or 3-aminopropyltrimethoxysilane through
condensation reaction, and then dehydrating, wherein R53 is
--CO(CH2)2CONH(CH2)3Si(X)3 or
--CO(CH2)3CONH(CH2)3Si(X)3, in which X is ethoxy
or methoxy.

61. A method for making the hybrid lipid compound of claim 53 comprises
following steps: 1) forming a compound 2 with a constructional formula
##STR00221## by reacting a compound 1 with a constructional formula
##STR00222## with a compound 4 with a constructional formula
##STR00223## in polar organic solvent under 25-70.degree. C. for 24-48
h, following washing in turn with acidic water and water, then
recrystallizing, wherein the molar ratio of the compound 1 to the
compound 4 is 1:1.5-4, a is 2 or 3, R1 is C.sub.6.about.C18
alkyl and R2 is C.sub.6.about.C18 alkyl; 2) forming a compound
6 with a constructional formula ##STR00224## by reacting the compound 2
with N,N-dicyclohexylcarbodiimide, 4-dimethylaminopyridine and a compound
5 with a constructional formula ##STR00225## in polar organic solvent
under 50-80.degree. C. for 12-36 h, wherein the molar ratio between the
compound 2, N,N'-dicyclohexylcarbodiimide, 4-dimethylaminopyridine and
the compound 5 is 1:1-3:0.8-1.2:3-6, R6 is --H, phenyl or --CH3
and R7 is --H, phenyl or --CH3; 3) forming a compound 7 with a
constructional formula ##STR00226## by reacting the compound 6 with
4-dimethylaminopyridine, deacid reagent and the compound 4 in aprotic
organic solvent under 25-70.degree. C. for 24-48 h, following washing in
turn with acidic water and water, and then purifying through column
chromatography, wherein the molar ratio between the compound 6,
4-dimethylaminopyridine, the deacid reagent and the compound 4 is
1:0.4-1:1-6:2-5, and a is 2 or 3; 4) forming a compound 8 with a
constructional formula ##STR00227## by reacting the compound 7 with
hydrogen in the presence of catalyst in a mixed reaction solvent of
tetrahydrofuran and methanol or ethanol under 25-80.degree. C. for 12-48
h, wherein the molar ratio of the compound 7 to the catalyst is
1:0.4-0.6, hydrogen pressure is 1.0-1.2 MPa, the volume ratio of
tetrahydrofuran to methanol or ethanol is 3-4:1, the catalyst is
palladium/carbon or palladium hydroxide/carbon; 5) forming a compound 10
with a constructional formula ##STR00228## by reacting a compound 9
with a constructional formula ##STR00229## with the compound 8 and
N,N'-dicyclohexylcarbodiimide in aprotic organic solvent under
25-45.degree. C. for 24-60 h, wherein X1 is --H, --CH3,
CH3O--, halogen or --NO2, Y1 is --H, --CH3,
CH3O-- or halogen, and the molar ratio between the compound 8,
N,N'-dicyclohexylcarbodiimide and the compound 9 is 1:1.2-1.5:1.1-2; 6)
forming a hybrid lipid compound with a constructional formula
##STR00230## by reacting a compound 11 with a constructional formula
##STR00231## with the compound 10 and dibutyltin dilaurate in aprotic
organic solvent under 40-70.degree. C. for 48-72 h, wherein the molar
ratio between the compound 10, the compound 11 and dibutyltin dilaurate
is 1:2-4:0.2-0.8, R31 is --CONH(CH2)3Si(X)3, in which
X is ethoxy or methoxy; or forming a compound 12 with a constructional
formula ##STR00232## by reacting the compound 10 with
4-dimethylaminopyridine, deacid reagent and the compound 4 in aprotic
organic solvent under 25-70.degree. C. for 24-48 h, following washing in
turn with acidic water and water, then purifying through column
chromatography, wherein R9 is --CO(CH2)2COOH or
--CO(CH2)3COOH, the molar ratio between the compound 10,
4-dimethylaminopyridine, the deacid reagent and the compound 4 is
1:0.8-2:3-8:4-8; finally, forming a hybrid lipid with a constructional
formula ##STR00233## by reacting a compound 13 with a constructional
formula ##STR00234## with the compound 12 and
N,N'-dicyclohexylcarbodiimide in aprotic organic solvent under
25-40.degree. C. for 24-36 h, wherein R32 is
--CO(CH2)2CONH(CH2)3Si(X)3 or
--CO(CH2)3CONH(CH2)3Si(X)3, in which X is ethoxy
or methoxy, and the molar ratio between the compound 12,
N,N'-dicyclohexylcarbodiimide and the compound 13 is 1:1-2:1.5-2.0.

62. A method for making the hybrid lipid compound of claim 55 comprises
following steps: 1) forming a compound 15 with a constructional formula
##STR00235## by reacting a compound 14 a constructional formula
##STR00236## with the compound 6, N,N'-dicyclohexylcarbodiimide and
4-dimethylaminopyridine in polar organic solvent under 50-80.degree. C.
for 12-36 h, wherein the molar ratio between the compound 6,
N,N'-dicyclohexylcarbodiimide, 4-dimethylaminopyridine and the compound
14 is 1:1-3:0.8-1.2:1-3, a is 2 or 3, R1 is
C.sub.6.quadrature.C18 alkyl, R2 is C.sub.6.quadrature.C18
alkylquadratureR6 is phenyl or --CH3 and R7 is --H or
--CH3; 2) forming a compound 16 with a constructional formula
##STR00237## by reacting the compound 15 with hydrogen in the presence
of catalyst in a mixed reaction solvent of tetrahydrofuran and methanol
or ethanol under 25-80.degree. C. for 12-48 h, wherein the molar ratio of
the compound 15 to catalyst is 1:0.4-0.6, hydrogen pressure is 1.0-1.2
MPa, the volume ratio of tetrahydrofuran to methanol or ethanol is 3-4:1,
the catalyst is palladium/carbon or palladium hydroxide/carbon; 3)
forming a hybrid lipid compound with a constructional formula
##STR00238## by reacting the compound 16 with the compound 11 and
dibutyltin dilaurate in aprotic organic solvent under 40-70.degree. C.
for 48-72 h, wherein R31 is --CONH(CH2)3Si(X)3, in
which X is ethoxy or methoxy, the molar ratio between the compound 16,
the compound 11 and dibutyltin dilaurate is 1:2-4:0.2-0.8; 4) forming a
compound 17 with a constructional formula ##STR00239## by reacting the
compound 16 with 4-dimethylaminopyridine, deacid reagent and the compound
4 in aprotic organic solvent under 25-70.degree. C. for 24-48 h,
following washing in turn with acidic water and water, then purifying
through column chromatography, wherein the molar ratio between the
compound 16, 4-dimethylaminopyridine, the deacid reagent and the compound
4 is 1:0.8-2:3-8:4-8, and a is 2 or 3; 5) forming a hybrid lipid compound
with a constructional formula ##STR00240## by reacting the compound 17
with the compound 13 and N,N'-dicyclohexylcarbodiimide in aprotic organic
solvent under 25-40.degree. C. for 24-36 h, wherein R32 is
--CO(CH2)2CONH(CH2)3Si(X)3 or
--CO(CH2)3CONH(CH2)3Si(X)3, in which X is ethoxy
or methoxy, and the molar ratio between the compound 17,
N,N'-dicyclohexylcarbodiimide and the compound 13 is 1:1-2:2.0-2.5.

63. A method for making the hybrid lipid compound of claim 56 comprises
following steps: 1) forming a compound 19 with a constructional formula
##STR00241## by reacting the compound 18 with a constructional formula
##STR00242## with the compound 8 and N,N'-dicyclohexylcarbodiimide in
aprotic organic solvent under 25-45.degree. C. for 24-72 h, wherein the
molar ratio between the compound 8, N,N'-dicyclohexylcarbodiimide and the
compound 18 is 1:1.2-1.5:1.1-2, a is 2 or 3, X2 is --H, --CH3,
CH3O-- or halogen, R1 is C.sub.6.quadrature.C18 alkyl, and
R2 is C.sub.6.quadrature.C18 alkyl; 2) forming a hybrid lipid
compound 20 with a constructional formula ##STR00243## by reacting the
compound 11 with the compound 19 and dibutyltin dilaurate in aprotic
organic solvent under 40-80.degree. C. for 36-72 h, wherein R31 is
--CONH(CH2)3Si(X)3, in which X is ethoxy or methoxy, the
molar ratio between the compound 19, the compound 11 and dibutyltin
dilaurate is 1:2-5:0.2-1.0; 3) forming a compound 21 with a
constructional formula ##STR00244## by reacting the compound 19 with
4-dimethylaminopyridine, deacid reagent and the compound 4 in aprotic
organic solvent under 25-70.degree. C. for 48-48 h, following washing in
turn with acidic water and water, then purifying through column
chromatography, wherein R9 is --CO(CH2)2COOH or
--CO(CH2)3COOH, the molar ratio between the compound 19,
4-dimethylaminopyridine, the deacid reagent and the compound 4 is
1:0.8-2:3-9:3-10, the deacid agent is triethylamine or pyridine; 4)
forming a hybrid lipid compound 22 with a constructional formula
##STR00245## by reacting the compound 21 with the compound 13 and
N,N'-dicyclohexylcarbodiimide in aprotic organic solvent under
25-45.degree. C. for 24-48 h, wherein R32 is
--CO(CH2)2CONH(CH2)3Si(X)3 or
--CO(CH2)3CONH(CH2)3Si(X)3, in which X is ethoxy
or methoxy, and the molar ratio between the compound 21,
N,N'-dicyclohexylcarbodiimide and the compound 13 is 1:1-2:1.5-2.0; 5)
forming a hybrid lipid compound with a constructional formula
##STR00246## by reacting a Metal salts 23 with a constructional formula
MY with the compound 20 in organic solvent under 25-180.degree. C. for
2-48 h, following removing reaction solvent in vacuum, later washing, the
crude product was then purified by column chromatography, wherein the
molar ratio the compound 20 and the compound 23 is 1:5-25, R31 is
--CONH(CH2)3Si(X)3, in which X is ethoxy or methoxy; or
forming a hybrid lipid compound with a constructional formula
##STR00247## by reacting a Metal salts 23 a constructional formula MY
with the compound 22 under 25-180.degree. C. for 2-48 h, following
removing reaction solvent in vacuum, later washing, the crude product was
then purified by column chromatography, wherein the molar ratio of the
compound 22 and the compound 23 is 1:5-25, R32 is
--CO(CH2)2CONH(CH2)3Si(X)3 or
--CO(CH2)3CONH(CH2)3Si(X)3, in which X is ethoxy
or methoxy; X2 is --H, --CH3, CH3O-- or halogen, M is the
metal ion coordinated with porphyrin ring, and Y is the anion which
formed metal salts with M.

64. A method for making the hybrid lipid compound of claim 57 comprises
following steps: 1) forming a compound 2 with a constructional formula
##STR00248## by reacting a compound 1 with a constructional formula
##STR00249## with a compound 4 a constructional formula ##STR00250##
in polar organic solvent under 25-70.degree. C. for 24-48 h, following
washing in turn with acidic water and water, then recrystallizing,
wherein the molar ratio of the compound 1 to the compound 4 is 1:1.5-4, a
is 2 or 3, R1 is C.sub.6.about.C18 alkyl, and R2 is
C.sub.6.about.C18 alkyl; 2) forming a compound 25 with a
constructional formula ##STR00251## by reacting a compound 24 with a
constructional formula ##STR00252## with the compound 2,
N,N'-dicyclohexylcarbodiimide and 4-dimethylaminopyridine in polar
organic solvent under 50-80.degree. C. for 12-36 h, wherein X1 is
--H, --CH3, CH3O--, halogen or --NO2 the molar ratio
between the compound 2, N,N'-dicyclohexylcarbodiimide,
4-dimethylaminopyridine and the compound 24 is 1:1-3:0.8-1.2:3-6; 3)
forming a hybrid lipid compound with a constructional formula
##STR00253## by reacting the compound 25, the compound 11 and dibutyltin
dilaurate in aprotic organic solvent under 40-70.degree. C. for 48-72 h,
wherein R31 is --CONH(CH2)3Si(X)3, in which X is
ethoxy or methoxy, and the molar ratio between the compound 25, the
compound 11 and dibutyltin dilaurate is 1:1-2:0.2-0.8; 4) forming a
compound 26 with a constructional formula ##STR00254## by reacting the
compound 25 with 4-dimethylaminopyridine, deacid reagent and the compound
4 in aprotic organic solvent under 25-70.degree. C. for 24-48 h,
following washing in turn with acidic water and water, then
recrystallizing, wherein the molar ratio between the compound 25,
4-dimethylaminopyridine, the deacid agent and the compound 4 is
1:0.4-1:1-6:2-5; 5) forming a hybrid lipid compound with a constructional
formula ##STR00255## by reacting the compound 26 with the compound 13
and N,N'-dicyclohexylcarbodiimide in aprotic organic solvent, under
25-40.degree. C. for 24-36 h, wherein R32 is
--CO(CH2)2CONH(CH2)3Si(X)3 or
--CO(CH2)3CONH(CH2)3Si(X)3, in which X is ethoxy
or methoxy; and the molar ratio between the compound 26,
N,N'-dicyclohexylcarbodiimide and the compound 13 is 1:1-2:1.1-1.5.

65. A method for making the hybrid lipid compound of claim 58 comprises
following steps: 1) forming a compound 27 with a constructional formula
##STR00256## by reacting pentaerythritol and alkyl bromide with a
constructional formula of R4--Br in alkaline condition through
nucleophilic substitution reaction, wherein the molar ratio of
pentaerythritol to alkyl bromide is 1:3, and R4 is
C.sub.6.quadrature.C18 alkyl; 2) forming a hybrid lipid compound
with a constructional formula ##STR00257## by reacting the compound 27
with 3-isocyanatopropyltriethoxysilane or
3-isocyanatopropyltrimethoxysilane through nucleophilic reactions,
wherein R51 is --CONH(CH2)3Si(X)3, in which X is
ethoxy or methoxy; or forming a hybrid lipid compound with a
constructional formula ##STR00258## by reacting the compound 27 with
6-Bromohexanoyl chloride through esterification reaction, following
reacting with dimethylamine gas saturated tetrahydrofuran solution
through nucleophilic reaction, and then reacting with
3-Bromopropyltriethoxysilane or 3-Bromopropyltrimethoxysilane through
nucleophilic reaction, wherein R52 is
--CO(CH2)5N(CH3)2(CH2)3Si(X)3Y, in
which X is ethoxy or methoxy and Y is halogenated group; or forming a
hybrid lipid compound with a constructional formula ##STR00259## by
reacting the compound 27 with succinic anhydride or glutaric anhydride
through nucleophilic reaction, following reacting with
3-aminopropyltriethoxysilane or 3-aminopropyltrimethoxysilane through
nucleophilic reaction, wherein R53 is
--CO(CH2)2CONH(CH2)3Si(X)3 or
--CO(CH2)3CONH(CH2)3Si(X)3, in which X is ethoxy
or methoxy.

66. A method for making the hybrid lipid compound of claim 59 comprises
following steps: 1) forming a compound 8 with a constructional formula
##STR00260## by reacting the compound 26 with hydrogen in the presence
of catalyst in a mixed reaction solvent of tetrahydrofuran and methanol
or ethanol under 25-80.degree. C. for 12-48 h, wherein the molar ratio of
the compound 26 to the catalyst is 1:0.4-0.6, hydrogen pressure is
1.0-1.2 MPa, the volume ratio of tetrahydrofuran to methanol or ethanol
is 3-4:1, the catalyst is palladium/carbon or palladium hydroxide/carbon,
a is 2 or 3, R1 is C.sub.6.about.C18 alkyl, and R2 is
C.sub.6.about.C18 alkyl; 2) forming a hybrid lipid compound 28 with
a constructional formula ##STR00261## by reacting the compound 13 with
a constructional formula ##STR00262## with the compound 8 and
N,N-dicyclohexylcarbodiimide in aprotic organic solvent under
25-40.degree. C. for 24-36 h, wherein the molar ratio between the
compound 8, N,N'-dicyclohexylcarbodiimide and the compound 13 is
1:1-2:1.1-1.5, and X is ethoxy or methoxy; 3) forming a hybrid lipid
compound with a constructional formula ##STR00263## by reacting the
compound 28 with deacid reagent, 4-dimethylaminopyridine and the compound
4 in aprotic organic solvent under 25-70.degree. C. for 24-48 h,
following washing in turn with acidic water and water, then purifying
through column chromatography, wherein R9 is
--CO(CH2)2COOH or --CO(CH2)3COOH, R8 is
--CO(CH2)2CONH(CH2)3Si(X)3 or
--CO(CH2)3CONH(CH2)3Si(X)3, in which X is ethoxy
or methoxy, a is 2 or 3, and the molar ratio of compound 28,
4-dimethylaminopyridine, the deacid reagent and the compound 4 is
1:0.4-1:1-6:4-8.

67. Use of the hybrid lipid compound based on pentaerythritol of claim 53
as light-control materials for controlling drug release from liposome.

68. Use of the hybrid lipid compound based on pentaerythritol of claim 56
in the preparation of the relevant liposome which is used as drug or drug
carriers for inflammatory diseases, neurological diseases,
atherosclerosis and cancer treatment.

69. Use of the hybrid lipid compound based on pentaerythritol in claim 56
in the preparation of the relevant liposome which is used as functional
materials for optical storage and molecular devices.

70. Use of the hybrid lipid compound based on pentaerythritol of claim 56
in the preparation of the relevant liposome which is used as functional
materials for simulation design and synthesis of artificial systems,
simulation of charge separation, electron transfer and signal
transduction.

71. Use of the hybrid lipid compound based on pentaerythritol of claim 52
in the preparation of the relevant liposome which is used as carriers of
various drugs.

72. Use of the hybrid lipid compound based on pentaerythritol of claim 53
in the preparation of the relevant liposome which is used as carriers of
various drugs.

73. Use of the hybrid lipid compound based on pentaerythritol of claim 54
in the preparation of the relevant liposome which is used as carriers of
various drugs.

74. Use of the hybrid lipid compound based on pentaerythritol of claim 55
in the preparation of the relevant liposome which is used as carriers of
various drugs.

75. Use of the hybrid lipid compound based on pentaerythritol of claim 56
in the preparation of the relevant liposome which is used as carriers of
various drugs.

76. Use of the hybrid lipid compound based on pentaerythritol of claim 57
in the preparation of the relevant liposome which is used as carriers of
various drugs.

77. Use of the hybrid lipid compound based on pentaerythritol of claim 58
in the preparation of the relevant liposome which is used as carriers of
various drugs.

78. Use of the hybrid lipid compound based on pentaerythritol of claim 59
in the preparation of the relevant liposome which is used as carriers of
various drugs.

79. Use of the hybrid lipid compound based on pentaerythritol of claim 53
in the preparation of nano-composite membrane materials.

80. Use of the hybrid lipid compound based on pentaerythritol of claim 55
in the preparation of nano-composite membrane materials.

81. Use of the hybrid lipid compound based on pentaerythritol of claim 56
in the preparation of nano-composite membrane materials.

82. Use of hybrid lipid compound based on pentaerythritol of claim 57 for
the removal of organic pollutants in the environment.

83. Use of hybrid lipid compound based on pentaerythritol of claim 58 for
the removal of organic pollutants in the environment.

84. Use of hybrid lipid compound based on pentaerythritol of claim 59 for
the removal of organic pollutants in the environment.

Description:

FIELD OF THE INVENTION

[0001] The present invention belongs to the field of biomedical materials
in materials science, specifically relates to hybrid lipid compounds,
intermediates, preparation methods and use thereof which these lipids use
pentaerythritol as the skeleton and contain aliphatic chain and siloxane
groups.

BACKGROUND OF THE PRESENT DISCLOSURE

[0002] Liposome is an artificial membrane, when the amphiphilic molecules
such as phospholipids and sphingolipids are dispersed in the aqueous
phase, the hydrophobic tails of the molecules tend to aggregate together
to prevent away from the aqueous phase, while the hydrophilic heads
expose to the aqueous phase, phospholipids in water spontaneously form
molecular organized assemblies relying on hydrophobic interaction, and
form a bilayer structure of closed vesicles. Liposomes consist of a
continuous bilayer or multi-layer lipid, each layer is lipid bilayer
membrane, interlayer and liposome core are the aqueous phase, while the
bilayer is the oil phase. Liposomes can be used as an experimental model
of biomembrane, they are often used as carriers of drugs, enzymes or
other agents in research and therapy, which are made more effective
delivery to the target cells, and released through cell fusion.

[0003] Liposome shows many advantages, such as simple preparation,
non-toxic and non-immunogenic response, in vivo degradation, easy to
accomplish targeting, improving and prolonging the drug efficacy,
moderating toxicity, avoiding drug resistance and changing the route of
drug administration. In addition, it shows amphiphilic properties,
hydrophilic and hydrophobic drugs can be both entrapped, water-soluble
drugs can be loaded into the aqueous phase of the liposome, and
oil-soluble drugs or amphiphilic drugs can be loaded into the lipid
bilayer, so liposome has broad applicability for various drugs. Since
1970s, liposomes have attracted much attention in the application of drug
carriers.

[0004] However, liposome has the limitation of instability which hampering
its practical application. Specifically during storage, liposome may be
destroyed due to the reasons of drug leakage, aggregation of particles
and oxidation or hydrolysis of phospholipids and so on. In the body, due
to the interaction with blood albumin, conditioning factors, antibodies
and other substances, liposome may be ruptured, causing rapid leakage of
encapsulated drugs, which was quickly degraded by some enzymes and
swallowed by some phagocytic cells, and can not effectively reach the
targeted tissue to play their role. Therefore, the development of stable
liposome as drug carriers is a prerequisite for practical application,
which showing great significance.

[0005] In recent years, a variety of functional liposomes have been
gradually developed, such as temperature-sensitive liposome, pH-sensitive
liposome, light-sensitive liposome and so on, resulting in possibility of
site-fixed, time-regular, quantitative release of the drug. Among them,
light-sensitive liposome has its unique advantages, when the drug is
embedded in such type of material and delivered into a specific location
of the body, configuration of light sensitive group can be changed simply
by external light irradiation, leading to controlled release of entrapped
drug. Currently, many of light-control materials reported are azobenzene
derivatives, introduction of azobenzene derivatives into liposome may
reach the results of site-fixed, time-regular, quantitative release of
drugs, but there are still some problems. For example, the use of
azobenzene-containing surfactants as light-control material is prone to
cause phase separation and fusion of liposome (Chem. Lett. (1981)
1001-1004), while the introduction of azobenzene containing phospholipids
as light-controlled release materials will decrease the stability of
liposome, lead to a sudden release of drugs, thus making it difficult for
practical application (Photochem. Photobiol. 62 (1995) 24-29).

[0006] Cholesterol is an important component of cell membranes, the most
important function of cholesterol is regulating physical and chemical
properties of cell membrane (Yeagle P L. Biochim Biophys Acta 1985, 822
(3-4), 267-87; Yeagle P L. In: Yeagle P L, editor. Biology of
cholesterol. Boca Raton (Fla., USA): CRC Press, 1988. p. 121-146). In the
cell membrane, cholesterol can interact with phospholipids or
sphingolipids membrane and thus affect their properties. Increased levels
of cholesterol in the lipid bilayer will expand and eventually eliminate
coordination of the gel liquid crystal phase transition of the lipid
bilayer (Lewis RNAH, McElhaney R N. In: Yegle P L, editor. The structure
of biological membranes. Boca Raton (Fla., USA): CRC Press, 1992. p.
73-156; Maulik P R, Shipley G G. Biophys J 1996, 70, 2256-2265).
Cholesterol in the phospholipid bilayer is presented at an intermediate
state, when above the phase transition temperature, the membrane fluidity
is decreased, and when below the phase transition temperature, the
membrane fluidity is increased (Demel R A, de Kruijff B. Biochim Biophys
Acta 1976, 457 (2), 109-132). In the biologically relevant liquid crystal
state, the arrangement of cholesterol in the membrane is relative
ordered, so that movement rate of the alkyl chain of phospholipids
decreases. In the membrane relatively ordered state, the membrane will be
made more dense, thereby the mechanical properties of the membrane is
increased and the permeation performance is decreased (Lund-Katz S,
Laboda H M, McLean L R, Phillips M C. Biochemistry 1988, 27 (9),
3416-3423). In addition, cholesterol in organisms and traditional
liposome is generally in a free state, in the practical research and
application, free cholesterol is tend to quickly move out from the
liposome membrane (Kan, C C; Yan, J.; Bittman, R. Biochemistry 1992, 31,
1866-1874; Hamilton, J A Curr. Opin. Lipidol. 2003, 14, 263-271), which
making the stability of liposomes decrease and the application of
liposome as drug carriers is severely limited.

[0007] Porphyrin and its derivatives are macrocyclic molecules containing
four conjugated pyrrole rings, it has a very wide range of applications
in medicine, biochemistry, analytical chemistry, synthetic chemistry,
materials science because of its unique performance and easy
modification, especially porphyrin derivatives have unique electronic
structure and optical properties, in recent years it have attracted much
attention in medicine, optical storage, molecular devices, simulation
design and synthesis of artificial systems for simulating charge
separation, electron transfer and signal transduction. However, porphyrin
derivative is generally rigid molecule, it is difficult to be molded, and
also its water solubility is relatively poor, which to some extent limit
its practical application (J. Photochem. Photobiol., B 2002, 66, 89-106).
In addition, when porphyrin derivatives including metal complexes are
directly applied to the organism, there are also many problems in the
safety and effectiveness.

[0008] The porphyrin molecule is embedded in the micelle, liposome,
low-density lipid protein, polymer micelles or hydrophilic polymers and
other carriers to improve its water solubility and biocompatibility. But
micelle carrier system is often prone to elicit acute hypersensibility
(anaphylactic) reactions in vivo (Br. Med. J. 1980, 280, 1353-1353),
liposome is prone to opsonization and subsequent capture by the major
defense system of the body (J. Pharm. Sci. 1995, 84, 166-173), and
polymer shows poor tumor regression and increased accumulation in normal
tissues (J. Pharm. Pharmacol. 2001, 53, 155-166). All the above carriers
have a common drawback, in which the porphyrin derivatives embedded is
easy to leak out, resulting in phototoxic side effects. The
carrier-embedded silica-based nanoparticles which with a high degree of
stability, good biocompatibility and water dispersion can overcome the
above disadvantages arising from other carriers and be easily modified
with different functional groups, and they are not vulnerable to
microbial attack. (J. Am. Chem. Soc. 2003, 125, 7860-7865).

[0009] In addition, encapsulation efficiency is a practical measurement
for liposome's application as drug carriers, there are many ways to
improve the encapsulation efficiency of liposome at present (Chinese
Pharmaceutical Industry 2002, 33 (11), 564-568), and the way through
intermolecular interactions or electrostatic attraction to improve
liposome's encapsulation efficiency has its significant advantages. Among
them, liposome with benzene ring can generate intermolecular conjugation
with a number of drugs with similar groups, such as camptothecin, etc.,
which effectively increase the drug-embedded efficiency (Journal of
Controlled Release, 2008, 127, 231-238). Liposome derived from lipid
containing carboxylic groups has many free carboxyl groups on the
surface, on one hand, it is facilitate to couple with drugs containing
hydroxyl or amino groups such as doxorubicin, on the other hand, such
liposome can take a wealth of negative charge under a specific pH values,
which well suited for the entrapment of drugs through electrostatic
attraction, thus the encapsulation and drug loading efficiency can be
greatly improved. Meanwhile, liposome with rich carboxyl groups on
surface can also facilitate the modification of a variety of targeting
molecules to improve their targeting effect.

[0010] Currently, most of the liposomes are prepared by phospholipid,
electrostatic, hydrophobic and van der Waals interaction between these
liposomes with plasma proteins, conditioning factors, antibodies and
other substances often lead to destabilization of liposomes, which
generally making liposomes be quickly removed before reaching the target
in the circulation and encapsulated drug be quickly released prior to
reaching their target tissue. This not only makes the drug unable
effectively play the role, but also may cause serious side effects. In
addition, the drug can interact with the phospholipid of liposome (for
example, anthracycline adriamycin showed surfactant or detergent-like
effect to the phospholipid bilayer), which will lead to drug leakage
during storage and make the liposome be more unstable. As the liposomes
have the shortcomings such as in vivo instability and storage
instability, thus limiting the clinical application and industrial
production of liposome. Although research of liposome has been carried
out for decades, but development of liposome-drug formulations is still
very few, poor stability of liposome is a serious problem in its
commercialization process. Therefore, the development of stable liposome
as drug carriers is a prerequisite to practical application, which
showing great significance.

[0011] Based on the above considerations, in the present invention the
inventors designed and synthesized a new class of hybrid lipids, the
molecular structure of such lipids contain --Si(OEt)3 or
--Si(OCH3)3 groups, in aqueous solution such lipids can
self-assemble to form vesicle structure with lipid bilayer, there is
stable Si--O--Si network structure on the vesicular surface and covalent
bonding with the surface of the liposome, which greatly enhancing its
stability and water solubility.

[0012] Based on these novel hybrid lipids, the inventors have made a
series of related research, for example, azobenzene unit was introduced
into the molecular structure of the novel hybrid lipids, the lipid
bilayer permeability can be easily controlled by light irradiation to
achieve controlled release of drugs; cholesterol groups was covalent
bonded with the novel hybrid lipids, lipid bilayer fluidity and
permeability can be further adjusted, thus formulation can effectively
prevent the loss of cholesterol and can be used as a model for studying
structure and function of cell membrane; benzene ring or carboxylic acid
group was bonded with new hybrid lipids, thus encapsulated hydrophobic or
hydrophilic drugs can be interacted by conjugated effects or
electrostatic attraction, thereby enhancing drug encapsulation
efficiency; functional porphyrin moiety was covalent bonded with the
novel hybrid lipids, which make the porphyrin unit be orderly arranged in
the bilayer structure of the formed vesicles, and then introduction of
different metals through the coordination will develop a series of
functional nanomaterials.

SUMMARY OF THE PRESENT INVENTION

[0013] The primary purpose of the present invention is to provide hybrid
lipid compounds based on pentaerythritol and their intermediates,
preparation methods and use thereof in view of the above problems, the
lipid in the present invention can be hydrolyzed and condensed to form
the corresponding liposome with silicate network surface (called
cerasome); the prepared cerasomes show advantages of high stability, good
biocompatibility, low toxicity and even non-toxicity and uneasy to
leakage of drug.

[0014] To achieve these goals, one aspect of the present invention
provides a hybrid lipid compound based on pentaerythritol with a
constructional formula

##STR00001##

Wherein:

[0015] R1 is C6˜C18 alkyl, R2 is
C6˜C18 alkyl, R5 is one among the group consisting
of --CO(CH2)5N(CH3)2(CH2)3Si(X)3Y,
--CO(CH2)2CONH(CH2)3Si(X)3,
--CO(CH2)3CONH(CH2)3Si(X)3 and
--CONH(CH2)3Si(X)3, in which X is ethoxy or methoxy, Y is
halogenated group; and a is 2 or 3.

[0016] Another aspect of the present invention provides a hybrid lipid
compound based on pentaerythritol with a constructional formula

##STR00002##

Wherein:

[0017] R1 is C6˜C18 alkyl, R2 is
C6˜C18 alkyl, R3 is one among the group consisting
of --CO(CH2)2CONH(CH2)3Si(X)3,
--CO(CH2)3CONH(CH2)3Si(X)3 and
--CONH(CH2)3Si(X)3, in which X is ethoxy or methoxy, a is
2 or 3, X1 is one among the group consisting of --H, --CH3,
CH3O--, halogenated group and --NO2, Y1 is one among the
group consisting of --H, --CH3, CH3O-- and halogenated group,
when Y1 is attached at the 2-position to the azobenzene unit,
Y1 is --H or halogenated group, while when Y1 is attached at
the 3-position of the azobenzene unit, Y1 is --H, --CH3, or
CH3O--.

[0018] Another aspect of the present invention provides a hybrid lipid
compound based on pentaerythritol with a constructional formula

##STR00003##

Wherein:

[0019] R1 is C6˜C18 alkyl, R2 is
C6˜C18 alkyl, R3 is one among the group consisting
of --CO(CH2)2CONH(CH2)3Si(X)3,
--CO(CH2)3CONH(CH2)3Si(X)3 and
--CONH(CH2)3Si(X)3, in which X is ethoxy or methoxy, and a
is 2 or 3.

[0020] Another aspect of the present invention provides a hybrid lipid
compound based on pentaerythritol with a constructional formula

##STR00004##

Wherein:

[0021] R1 is C6˜C18 alkyl, R2 is
C6˜C18 alkyl, R3 is one among the group consisting
of --CO(CH2)2CONH(CH2)3Si(X)3,
--CO(CH2)3CONH(CH2)3Si(X)3 and
--CONH(CH2)3Si(X)3, in which X is ethoxy or methoxy, a is
2 or 3; X2 is one among the group consisting of --H, --CH3,
CH3O-- and halogenated group; M is metal ion coordinated with
porphyrin ring, M is one among the group consisting of Iron, Zinc,
Magnesium, Manganese, Cobalt, Copper, Molybdenum, Chromium, Gadolinium,
Nickel, Vanadium, Aluminum, Gallium and Iridium.

[0022] Another aspect of the present invention provides a hybrid lipid
compound based on pentaerythritol with a constructional formula

##STR00005##

Wherein:

[0023] R1 is C6˜C18 alkyl, R2 is
C6˜C18 alkyl, R3 is one among the group consisting
of --CO(CH2)2CONH(CH2)3Si(X)3,
--CO(CH2)3CONH(CH2)3Si(X)3 and
--CONH(CH2)3Si(X)3, in which X is ethoxy or methoxy, a is
2 or 3. X1 is one among the group consisting of --H, --CH3,
CH3O--, halogenated group and --NO2.

[0024] Another aspect of the present invention provides a hybrid lipid
compound based on pentaerythritol with a constructional formula

##STR00006##

Wherein:

[0025] R4 is C6˜C18 alkyl, R5 is one among the
group consisting of
--CO(CH2)5N(CH3)2(CH2)3Si(X)3Y,
--CO(CH2)2CONH(CH2)3Si(X)3,
--CO(CH2)3CONH(CH2)3Si(X)3 and
--CONH(CH2)3Si(X)3, in which X is ethoxy or methoxy, Y is
halogenated group.

[0026] Another aspect of the present invention provides a hybrid lipid
compound based on pentaerythritol with a constructional formula

##STR00007##

Wherein:

[0027] R1 is C6˜C18 alkyl, R2 is
C6˜C18 alkyl, R8 is one among the group consisting
of CO(CH2)2CONH(CH2)3Si(X)3,
--CO(CH2)3CONH(CH2)3Si(X)3 and
--CONH(CH2)3Si(X)3, in which X is ethoxy or methoxy,
R9 is selected among the group consisting of
--CO(CH2)2COOH and --CO(CH2)3COOH; a is 2 or 3.

[0028] Wherein, the said halogenated group is selected among the group
consisting of Fluorine, Chlorine, Bromine, Iodine.

[0029] In particular, R1 is one among the group consisting of hexyl,
octyl, undecyl, dodecyl, tridecyl, tetradecyl, fifteen alkyl, hexadecyl,
seventeen alkyl and octadecyl. R2 is one among the group consisting
of hexyl, octyl, undecyl, dodecyl, tridecyl, tetradecyl, fifteen alkyl,
hexadecyl, seventeen alkyl and octadecyl.

[0030] Another aspect of the present invention provides a preparation
method of a hybrid lipid compound based on pentaerythritol with a
constructional formula

##STR00008##

which comprises following steps: 1) forming a compound 1 with a
constructional formula

##STR00009##

by reacting alkyl amines and alkyl bromide under reflux through
substitution reaction, wherein the alkyl amines is R1--NH2, and
the alkyl bromide is R2--Br, in which R1 is
C6˜C18, alkyl chains and R2 is
C6˜C18 alkyl chains; 2) forming a compound with a
constructional formula

##STR00010##

by reacting the compound 1 with succinic anhydride or glutaric anhydride
through nucleophilic reaction, wherein, a is 2 or 3; then forming a
compound with a constructional formula

##STR00011##

by reacting the compound 2 with excess 4 to 6 times of pentaerythritol
through esterification reaction, wherein a is 2 or 3; 3) forming a hybrid
lipid compound with a constructional formula

##STR00012##

by reacting the compound 3 with 3-Isocyanatopropyltriethoxysilane or
3-Isocyanatopropyltrimethoxysilane through nucleophilic reaction, wherein
R51 is --CONH(CH2)3Si(X)3, in which X is ethoxy or
methoxy; or forming a hybrid lipid compound with a constructional formula

##STR00013##

by reacting the compound 3 with 6-Bromohexanoyl chloride through
esterification reaction, following reacting with dimethylamine gas
saturated tetrahydrofuran solution through nucleophilic reaction, and
then reacting with 3-Bromopropyltriethoxysilane or
3-Bromopropyltrimethoxysilane through nucleophilic reaction, wherein
R52 is
--CO(CH2)5N(CH3)2(CH2)3Si(X)3Y, X is
ethoxy or methoxy, and Y is halogenated group; or forming a hybrid lipid
compound with a constructional formula

##STR00014##

by reacting the compound 3 with succinic anhydride or glutaric anhydride
through nucleophilic reaction, following reacting with
3-aminopropyltriethoxysilane or 3-aminopropyltrimethoxysilane through
condensation reaction, and then dehydrating, wherein R53 is one
among the group consisting of
--CO(CH2)2CONH(CH2)3Si(X)3 and
--CO(CH2)3CONH(CH2)3Si(X)3, in which X is ethoxy
or methoxy.

[0031] Wherein, the said halogenated group is one among the group
consisting of Fluorine, Chlorine, Bromine, Iodine.

[0032] In particular, R1 is one among the group consisting of hexyl,
octyl, undecyl, dodecyl, tridecyl, tetradecyl, fifteen alkyl, hexadecyl,
seventeen alkyl and octadecyl. R2 is one among the group consisting
of hexyl, octyl, undecyl, dodecyl, tridecyl, tetradecyl, fifteen alkyl,
hexadecyl, seventeen alkyl and octadecyl.

[0033] Wherein, the time of the said refluxing in step "1)" is 5 days, the
reaction time in step "3)" is 2-3 days.

[0034] Another aspect of the present invention provides a preparation
method of a hybrid lipid compound based on pentaerythritol with a
constructional formula

##STR00015##

which comprises following steps: 1) forming a compound 2 with a
constructional formula

##STR00016##

by reacting a compound 1 with a constructional formula

##STR00017##

with a compound 4 with a constructional formula

##STR00018##

in polar organic solvent under 25-70quadrature for 24-48 h, following
washing in turn with acidic water and water, and then recrystallizing,
wherein the molar ratio of the compound 1 to the compound 4 is 1:1.5-4, a
is 2 or 3; 2) forming a compound 6 with a constructional formula

##STR00019##

by reacting the compound 2 with N,N'-dicyclohexylcarbodiimide (DCC),
4-dimethylaminopyridine (DMAP) and a compound 5 with a constructional
formula

##STR00020##

in polar organic solvent under 50-80quadrature for 12-36 h, wherein the
molar ratio the compound 2, DCC, DMAP and the compound 5 is
1:1-3:0.8-1.2:3-6, R6 is one among the group consisting of --H,
phenyl and --CH3, R7 is one among the group consisting of --H,
phenyl and --CH3; 3) forming a compound 7 with a constructional
formula

##STR00021##

by reacting the compound 6 with 4-dimethylaminopyridine (DMAP), deacid
reagent and the compound 4 in aprotic organic solvent under
25-70quadrature for 24-48 h, following washing in turn with acidic
water and water, and then purifying through column chromatography,
wherein the molar ratio between the compound 6, DMAP, deacid reagent and
the compound 4 is 1:0.4-1:1-6:2-5, and a is 2 or 3. 4) forming a compound
8 with a constructional formula

##STR00022##

by reacting the compound 7 with hydrogen in the presence of catalyst in a
mixed reaction solvent of tetrahydrofuran and methanol or ethanol under
25-80quadrature for 12-48 h, wherein the molar ratio of the compound 7
to the catalyst is 1:0.4-0.6, hydrogen pressure is 1.0-1.2 MPa, the
volume ratio of tetrahydrofuran to methanol or ethanol is 3-4:1, the
catalyst is palladium/carbon or palladium hydroxide/carbon; 5) forming a
compound 10 with a constructional formula

##STR00023##

by reacting a compound 9 with a constructional formula

##STR00024##

with the compound 8 and DCC in aprotic organic solvent under
25-45quadrature for 24-60 h, wherein the molar ratio between the
compound 8, DCC and the compound 9 is 1:1.2-1.5:1.1-2; 6) forming a
hybrid lipid compound with a constructional formula

##STR00025##

by reacting a compound 11 with a constructional formula

##STR00026##

with the compound 10 and dibutyltin dilaurate in aprotic organic solvents
under 40-70quadrature for 48-72 h, wherein the molar ratio between the
compound 10, the compound 11 and Dibutyltin dilaurate is 1:2-4:0.2-0.8,
R31 is --CONH(CH2)3Si(X)3, in which X is ethoxy or
methoxy; or forming a compound 12 with a constructional formula

##STR00027##

by reacting the compound 10 with DMAP, deacid reagent and the compound 4
in aprotic organic solvent under 25-70quadrature for 24-48 h, following
washing in turn with acidic water and water, and then purifying through
Column column chromatography, wherein R9 is one among the group
consisting of --CO(CH2)2COOH and --CO(CH2)3COOH, the
molar ratio between the compound 10, DMAP, deacid reagent and the
compound 4 is 1:0.8-2:3-8:4-8; finally, forming a hybrid lipid compound
with a constructional formula

##STR00028##

by reacting a compound 13 with a constructional formula

##STR00029##

with the compound 12 and DCC in aprotic organic solvent under
25-40quadrature for 24-36 h, wherein R32 is one among the group
consisting of --CO(CH2)2CONH(CH2)3Si(X)3 and
--CO(CH2)3CONH(CH2)3Si(X)3, in which X is ethoxy
or methoxy, the molar ratio between the compound 12, DCC and the compound
13 is 1:1-2:1.5-2.0.

[0035] Wherein, when Y1 is attached at the 2-position to the
azobenzene unit, Y1 is --H, or halogenated group; when Y1 is
attached at the 3-position of the azobenzene unit, Y1 is --H,
--CH3, or CH3O--.

[0036] Wherein, R7 is --H when R6 is phenyl, or R7 is
--CH3 when R6 is --CH3.

[0037] Wherein, the said halogenated group is one among the group
consisting of Fluorine, Chlorine, Bromine, Iodine; R1 is one among
the group consisting of hexyl, octyl, undecyl, dodecyl, tridecyl,
tetradecyl, fifteen alkyl, hexadecyl, seventeen alkyl and octadecyl;
R2 is selected among the groups consisting of hexyl, octyl, undecyl,
dodecyl, tridecyl, tetradecyl, fifteen alkyl, hexadecyl, seventeen alkyl
and octadecyl.

[0038] Wherein, the polar organic solvent in step "1)" is one among the
group consisting of tetrahydrofuran, acetone, dimethylformamide and
acetonitrile, the molar ratio of the compound 1 to the compound 4 is
1:2-2.5.

[0039] The polar organic solvent in step "2)" is one among the group
consisting of tetrahydrofuran, acetone, dimethylformamide and
acetonitrile, the molar ratio of the compound 2, DCC, DMAP and the
compound 5 is 1:1.5-2:0.9-1.1:4-5.

[0040] In step "3)", the molar ratio of the compound 6, DMAP, deacid agent
and the compound 4 is 1:0.4-0.6:3-5:3-4.

[0041] In step "6)", the molar ratio of the compound 10, the compound 11
and Dibutyltin dilaurate is 1:2-2.5:0.3-0.5, the molar ratio of the
compound 10, DMAP, the deacid agent and the compound 4 is
1:1-1.5:5-6:6-7.

[0042] In particular, the said deacid agent is triethylamine or pyridine.

[0043] In particular, the said polar organic solvent is one among the
group consisting of tetrahydrofuran, acetone, dimethylformamide and
acetonitrile, the said aprotic organic solvent is one among the group
consisting of benzene, toluene, methylene chloride, chloroform, DMSO and
DMF.

[0044] Another aspect of the present invention provides a preparation
method of a hybrid lipid compound based on pentaerythritol with a
constructional formula

##STR00030##

which comprises following steps: 1) forming a compound 15 with a
constructional formula

##STR00031##

by reacting a compound 14 with a constructional formula

##STR00032##

with the compound 6, DCC and DMAP in polar organic solvents under
50-80quadrature for 12-36 h, wherein the molar ratio between the
compound 6, DCC, DMAP and the compound 14 is 1:1-3:0.8-1.2:1-3, a is 2 or
3, R6 is phenyl or --CH3,

R7 is --H or --CH3;

[0045] 2) forming a compound 16 with a constructional formula

##STR00033##

by reacting the compound 15 with hydrogen in the presence of catalyst in
a mixed reaction solvent of tetrahydrofuran and methanol or ethanol under
25-80quadrature for 12-48 h, wherein the molar ratio of the compound 15
to catalyst is 1:0.4-0.6, hydrogen pressure is 1.0-1.2 MPa, the volume
ratio of tetrahydrofuran to methanol or ethanol is 3-4:1, the catalyst is
palladium/carbon or palladium hydroxide/carbon; 3) forming a hybrid lipid
compound with a constructional formula

##STR00034##

by reacting the compound 16 with the compound 11 and Dibutyltin dilaurate
in aprotic organic solvent under 40-70quadrature for 48-72 h, wherein
R31 is --CONH(CH2)3Si(X)3, in which X is ethoxy or
methoxy, the molar ratio between the compound 16, the compound 11 and
Dibutyltin dilaurate is 1:2-4:0.2-0.8; 4) forming a compound 17 with a
constructional formula

##STR00035##

by reacting the compound 16 with DMAP, deacid reagent and the compound 4
in aprotic organic solvents under 25-70quadrature for 24-48 h,
following washing in turn with acidic water and water, and then purifying
through column chromatography, wherein the molar ratio between the
compound 16, DMAP, the deacid reagent and the compound 4 is
1:0.8-2:3-8:4-8, a is 2 or 3; 5) forming a hybrid lipid compound with a
constructional formula

##STR00036##

by reacting the compound 17 with the compound 13 and DCC in aprotic
organic solvent under 25-40quadrature for 24-36 h, wherein R32 is
one among the group consisting of
--CO(CH2)2CONH(CH2)3Si(X)3 and
--CO(CH2)3CONH(CH2)3Si(X)3, in which X is ethoxy
or methoxy, the molar ratio between the compound 17, DCC and the compound
13 is 1:1-2:2.0-2.5.

[0046] Wherein, R1 is one among the group consisting of hexyl, octyl,
undecyl, dodecyl, tridecyl, tetradecyl, fifteen alkyl, hexadecyl,
seventeen alkyl and octadecyl; R2 is one among the group consisting
of hexyl, octyl, undecyl, dodecyl, tridecyl, tetradecyl, fifteen alkyl,
hexadecyl, seventeen alkyl and octadecyl.

[0047] Wherein, the said polar organic solvent in step "1)" is one among
the group consisting of tetrahydrofuran, acetone, dimethylformamide and
acetonitrile, the molar ratio between the compound 6, DCC DMAP and the
compound 14 is 1:1.5-2:0.9-1.1:1.2-2.5; in step "3)", the molar ratio
between the compound 16, the compound 11 and dibutyltin dilaurate is
1:2-2.5:0.3-0.5; in step "4)", the said deacid agent is triethylamine or
pyridine, the molar ratio between the compound 16, DMAP, the deacid agent
and the compound 4 is 1:1-1.5:5-6:6-7.

[0048] In particularly, the said polar organic solvent is one among the
group consisting of tetrahydrofuran, acetone, dimethylformamide and
acetonitrile, the said aprotic organic solvent is one among the group
consisting of benzene, toluene, methylene chloride, chloroform, DMSO and
DMF.

[0049] Another aspect of the present invention provides a preparation
method of a hybrid lipid compound based on pentaerythritol with a
constructional formula

##STR00037##

which comprises following steps: 1) forming a compound 19 with a
constructional formula

##STR00038##

by reacting a compound 18 with a constructional formula

##STR00039##

with the compound 8 and DCC in aprotic organic solvents under
25-45quadrature for 24-72 h, wherein the molar ratio between the
compound 8, DCC and the compound 18 is 1:1.2-1.5:1.1-2, a is 2 or 3,
X2 is one among the group consisting of --H, --CH3, CH3O--
and halogen; 2) forming a hybrid lipid compound 20 with a constructional
formula

##STR00040##

by reacting the compound 11 with the compound 19 and dibutyltin dilaurate
in aprotic organic solvents under 40-80 for 36-72 h, wherein R31 is
--CONH(CH2)3Si(X)3, in which X is ethoxy or methoxy, the
molar ratio between the compound 19, the compound 11 and dibutyltin
dilaurate is 1:2-5:0.2-1.0; 3) forming a compound 21 with a
constructional formula

##STR00041##

by reacting the compound 19 with DMAP, deacid reagent and the compound 4
in aprotic organic solvent under 25-70 for 24-48 h, following washing in
turn with acidic water and water, then purifying through Column
chromatography, wherein R9 is selected among the group consisting of
--CO(CH2)2COOH and --CO(CH2)3COOH, the molar ratio
between the compound 19, DMAP, the deacid reagent and the compound 4 is
1:0.8-2:3-9:3-10, the deacid agent is triethylamine or pyridine; 4)
forming a hybrid lipid compound 22 with a constructional formula

##STR00042##

by reacting the compound 13 with compound 21 and DCC in aprotic organic
solvents under 25-45quadrature for 24-48 h, wherein R32 is
selected among the group consisting of
--CO(CH2)2CONH(CH2)3Si(X)3 and
--CO(CH2)3CONH(CH2)3Si(X)3, in which X is ethoxy
or methoxy, the molar ratio between the compound 21, DCC and the compound
13 is 1:1-2:1.5-2.0; 5) forming a hybrid lipid compound with a
constructional formula

##STR00043##

by reacting a Metal salts compound 23 having the formula of MY2 with
the compound 20 in organic solvent under 25-180quadrature for 2-48 h,
and later removing reaction solvent in vacuum, then washing, the crude
product was purified by column chromatography, wherein the molar ratio of
the compound 20 and the compound 23 is 1:5-25, R31 is
--CONH(CH2)3Si(X)3, in which X is ethoxy or methoxy; or
forming a hybrid lipid compound with a constructional formula

##STR00044##

by reacting a Metal salts compound 23 having the formula of MY2 with
the compound 22 under 25-180quadrature for 2-48 h, following removing
reaction solvent in vacuum, later washing with water, the crude product
was then purified by column chromatography, wherein the molar ratio of
the compound 22 and the compound 23 is 1:5-25, R32 is one among the
group consisting of --CO(CH2)2CONH(CH2)3Si(X)3
and --CO(CH2)3CONH(CH2)3Si(X)3, in which X is
ethoxy or methoxy; X2 is one among the group consisting of --H,
--CH3, CH3O-- and halogen, M is the metal ion coordinated with
porphyrin ring, and Y2 is the anion which formed metal salts with M.

[0050] Wherein, the said halogenated group is one among the group
consisting of Fluorine, Chlorine, Bromine, Iodine, R1 is one among
the group consisting of hexyl, octyl, undecyl, dodecyl, tridecyl,
tetradecyl, fifteen alkyl, hexadecyl, seventeen alkyl or octadecyl;
R2 is one among the group consisting of hexyl, octyl, undecyl,
dodecyl, tridecyl, tetradecyl, fifteen alkyl, hexadecyl, seventeen alkyl
or octadecyl; M is one among the group consisting of Iron, Zinc,
Magnesium, Manganese, Cobalt, Copper, Molybdenum, Chromium, Gadolinium,
Nickel, Vanadium, Aluminum, Gallium or Iridium; The anion is halogen
anion or acetate ion.

[0051] In particularly, the said apolatic organic solvent is one among the
group consisting of benzene, toluene, dichloromethane, chloroform, DMSO
and DMF.

[0052] In step "2)", wherein the molar ratio of the compound 19, the
compound 11 and dibutyltin dilaurate is 1:2-3:0.3-0.6; in step "3)",
wherein the molar ratio of the compound 19, DMAP, the deacid agent and
the compound 4 is 1:1-1.5:5-6:5-8; in step "5)", wherein the apolatic
organic solvent is one among DMSO, dimethyl formamide, methanol, ethanol,
methylene chloride and chloroform; in step "5", wherein the molar ratio
of the compound 20 to the compound 23 is 1:10-15, and the molar ratio of
the compound 22 to the compound 23 is 1:10-15.

[0053] Another aspect of the present invention provides a preparation
method of a hybrid lipid compound based on pentaerythritol with a
constructional formula

##STR00045##

which comprises following steps: 1) forming a compound 2 with a
constructional formula

##STR00046##

by reacting a compound 1 with a constructional formula

##STR00047##

with a compound 4 a constructional formula

##STR00048##

in polar organic solvent under 25-70° C. for 24-48 h, following
washing in turn with acidic water and water, then recrystallizing,
wherein the molar ratio of the compound 1 to the compound 4 is 1:1.5-4, a
is 2 or 3, R1 is C6˜C18 alkyl, and R2 is
C6˜C18 alkyl; 2) forming a compound 25 with a
constructional formula

##STR00049##

by reacting a compound 24 with a constructional formula

##STR00050##

with the compound 2, N,N'-dicyclohexylcarbodiimide and
4-dimethylaminopyridine in polar organic solvent under 50-80° C.
for 12-36 h, wherein X1 is --H, --CH3, CH3O--, halogen or
--NO2, the molar ratio between the compound 2,
N,N'-dicyclohexylcarbodiimide, 4-dimethylaminopyridine and the compound
24 is 1:1-3:0.8-1.2:3-6; 3) forming a hybrid lipid compound with a
constructional formula

##STR00051##

by reacting the compound 25, the compound 11 and dibutyltin dilaurate in
nonpolar organic solvent under 40-70° C. for 48-72 h, wherein
R31 is --CONH(CH2)3Si(X)3, in which X is ethoxy or
methoxy, and the molar ratio between the compound 25, the compound 11 and
dibutyltin dilaurate is 1:1-2:0.2-0.8; 4) forming a compound 26 with a
constructional formula

##STR00052##

by reacting the compound 25 with 4-dimethylaminopyridine, deacid reagent
and the compound 4 in aprotic organic solvent under 25-70° C. for
24-48 h, following washing in turn with acidic water and water, then
recrystallizing, wherein the molar ratio between the compound 25,
4-dimethylaminopyridine, the deacid agent and the compound 4 is
1:0.4-1:1-6:2-5; 5) forming a hybrid lipid compound with a constructional
formula

##STR00053##

by reacting the compound 26 with the compound 13 and
N,N'-dicyclohexylcarbodiimide in aprotic organic solvent, under
25-40° C. for 24-36 h, wherein R32 is
--CO(CH2)2CONH(CH2)3Si(X)3 or
--CO(CH2)3CONH(CH2)3Si(X)3, in which X is ethoxy
or methoxy; and the molar ratio between the compound 26,
N,N'-dicyclohexylcarbodiimide and the compound 13 is 1:1-2:1.1-1.5.

[0054] Wherein, in step "1)", the molar ratio of the compound 1 to the
compound 4 is 1:2-2.5; in step "2)", the molar ratio between the compound
2, DCC, DMAP and the compound 24 is 1:1.5-2:0.9-1.1:4-5; in step "3)",
the molar ratio between the compound 25, the compound 11 and dibutyltin
dilaurate is 1:1-1.25:0.3-0.5; in step "4", the molar ratio between the
compound 25, DMAP, the deacid agent and the compound 4 is
1:0.4-0.6:3-5:3-4.

[0055] In particularly, the said polar organic solvent is one among the
group consisting of tetrahydrofuran, acetone, dimethylformamide and
acetonitrile; the said apolatic organic solvent is one among the group
consisting of Benzene, toluene, dichloromethane, chloroform, DMSO and
DMF; the deacid agent is triethylamine or pyridine.

[0056] Another aspect of the present invention provides a preparation
method of a hybrid lipid based on pentaerythritol with a constructional
formula

##STR00054##

which comprises following steps: 1) forming a compound 27 with a
constructional formula

##STR00055##

by reacting pentaerythritol and alkyl bromide with a constructional
formula of R4--Br in alkaline condition through nucleophilic
substitution reaction, wherein the molar ratio of pentaerythritol to
alkyl bromide is 1:3, and R4 is C6˜C18 alkyl; 2)
forming a hybrid lipid compound with a constructional formula

##STR00056##

by reacting the compound 27 with 3-isocyanatopropyltriethoxysilane or
3-isocyanatopropyltrimethoxysilane through nucleophilic reactions,
wherein R51 is --CONH(CH2)3Si(X)3, in which X is
ethoxy or methoxy; or forming a hybrid lipid compound with a
constructional formula

##STR00057##

by reacting the compound 27 with 6-Bromohexanoyl chloride through
esterification reaction, following reacting with dimethylamine gas
saturated tetrahydrofuran solution through nucleophilic reaction, and
then reacting with 3-Bromopropyltriethoxysilane or
3-Bromopropyltrimethoxysilane through nucleophilic reaction, wherein
R52 is
--CO(CH2)5N(CH3)2(CH2)3Si(X)3Y, in
which X is ethoxy or methoxy and Y is halogenated group; or forming a
hybrid lipid compound with a constructional formula

##STR00058##

by reacting the compound 27 with succinic anhydride or glutaric anhydride
through nucleophilic reaction, following reacting with
3-aminopropyltriethoxysilane or 3-aminopropyltrimethoxysilane through
nucleophilic reaction, wherein R53 is
--CO(CH2)2CONH(CH2)3Si(X)3 or
--CO(CH2)3CONH(CH2)3Si(X)3, in which X is ethoxy
or methoxy.

[0057] Wherein, the said halogenated group is one among the group
consisting of Fluorine, Chlorine, Bromine, Iodine; R4 is one among
the group consisting of hexyl, octyl, undecyl, dodecyl, tridecyl,
tetradecyl, fifteen alkyl, hexadecyl, seventeen alkyl or octadecyl.

[0058] Another aspect of the present invention provides a preparation
method of a hybrid lipid based on pentaerythritol with a constructional
formula

##STR00059##

which comprises following steps: 1) forming a compound 8 with a
constructional formula

##STR00060##

by reacting the compound 26 with hydrogen in the presence of catalyst in
a mixed reaction solvent of tetrahydrofuran and methanol or ethanol under
25-80° C. for 12-48 h, wherein the molar ratio of the compound 26
to the catalyst is 1:0.4-0.6, hydrogen pressure is 1.0-1.2 MPa, the
volume ratio of tetrahydrofuran to methanol or ethanol is 3-4:1, the
catalyst is palladium/carbon or palladium hydroxide/carbon, a is 2 or 3,
R1 is C6˜C18 alkyl, and R2 is
C6˜C18 alkyl; 2) forming a hybrid lipid compound 28 with
a constructional formula

##STR00061##

by reacting the compound 13 with a constructional formula

##STR00062##

with the compound 8 and N,N'-dicyclohexylcarbodiimide in aprotic organic
solvent under 25-40° C. for 24-36 h, wherein the molar ratio
between the compound 8, N,N'-dicyclohexylcarbodiimide and the compound 13
is 1:1-2:1.1-1.5, and X is ethoxy or methoxy; 3) forming a hybrid lipid
compound with a constructional formula

##STR00063##

by reacting the compound 28 with deacid reagent, 4-dimethylaminopyridine
and the compound 4 in aprotic organic solvent under 25-70° C. for
24-48 h, following washing in turn with acidic water and water, then
purifying through column chromatography, wherein R9 is
--CO(CH2)2COOH or --CO(CH2)3COOH, R8 is
--CO(CH2)2CONH(CH2)3Si(X)3 or
--CO(CH2)3CONH(CH2)3Si(X)3, in which X is ethoxy
or methoxy, a is 2 or 3, and the molar ratio of compound 28,
4-dimethylaminopyridine, the deacid reagent and the compound 4 is
1:0.4-1:1-6:4-8.

[0059] Wherein, in step "3)", the molar ratio of the compound 28, DMAP,
the deacid agent and the compound 4 is 1:0.4-0.6:3-5:5-7.

[0060] In particularly, the polar organic solvent is one among the group
consisting of tetrahydrofuran, acetone, dimethylformamide and
acetonitrile; the aprotic organic solvent is one among the group
consisting of Benzene, toluene, Dichloromethane, chloroform, DMSO and
DMF; the deacid agent is triethylamine or pyridine.

[0061] Wherein, R1 is one among the group consisting of hexyl, octyl,
undecyl, dodecyl, tridecyl, tetradecyl, fifteen alkyl, hexadecyl,
seventeen alkyl and octadecyl; R2 is one among the group consisting
of hexyl, octyl, undecyl, dodecyl, tridecyl, tetradecyl, fifteen alkyl,
hexadecyl, seventeen alkyl and octadecyl.

[0062] Another aspect of the present invention is to provide the cerasome
self-assembly from the above hybrid lipids based on pentaerythritol by
sol-gel reaction.

[0063] Wherein any cerasome derived from the hybrid lipid compounds based
on pentaerythritol, have a silicate network surface.

[0064] Another aspect of the present invention provides use of the hybrid
lipid compound based on pentaerythritol as light-control materials for
controlling drug release from the liposome, the hybrid lipid compound
with a constructional formula

##STR00064##

Wherein:

[0065] R1 is C6˜C18 alkyl, R2 is
C6˜C18 alkyl, R3 is one among the group consisting
of --CO(CH2)2CONH(CH2)3Si(X)3,
--CO(CH2)3CONH(CH2)3Si(X)3 and
--CONH(CH2)3Si(X)3, in which X is ethoxy or methoxy, a is
2 or 3, X1 is one among the group consisting of --H, --CH3,
CH3O--, halogenated group and --NO2; Y1 is one among the
group consisting of --H, --CH3, CH3O-- and halogenated group.

[0066] Another aspect of the present invention provides use of hybrid
lipid compound based on pentaerythritol, wherein the cerasome derived
from the hybrid lipid compound is used as drug or drug carrier for
Inflammatory diseases, neurological diseases, atherosclerosis and cancer
treatment, the hybrid lipid compound with a constructional formula

##STR00065##

Wherein R1 is C6˜C18 alkyl, R2 is
C6˜C18 alkyl, R3 is one among the group consisting
of --CO(CH2)2CONH(CH2)3Si(X)3,
--CO(CH2)3CONH(CH2)3Si(X)3 and
--CONH(CH2)3Si(X)3, in which X is ethoxy or methoxy;
X2 is one among the group consisting of --H, --CH3, CH3O--
and halogen; M is the metal ion coordinated with porphyrin ring.

[0067] Another aspect of the present invention provides use of hybrid
lipid compound based on pentaerythritol, wherein the cerasome derived
from the hybrid lipid compound is used as functional materials for
optical storage and molecular devices, the hybrid lipid compound with a
constructional formula

##STR00066##

[0068] Wherein R1 is C6˜C18 alkyl, R2 is
C6˜C18 alkyl, R3 is one among the group consisting
of --CO(CH2)2CONH(CH2)3Si(X)3,
O(CH2)3CONH(CH2)3Si(X)3 and
--CONH(CH2)3Si(X)3, in which X is ethoxy or methoxy;
X2 is one among the group consisting of --H, --CH3, CH3O--
and halogen; M is the metal ion coordinated with porphyrin ring.

[0069] Another aspect of the present invention provides use of hybrid
lipid compound based on pentaerythritol, wherein the liposome derived
from the hybrid lipid compound is used as functional materials for
simulation design and synthesis of artificial systems, the hybrid lipid
compound with a constructional formula

##STR00067##

Wherein R1 is C6˜C18 alkyl, R2 is
C6˜C18 alkyl, R3 is one among the group consisting
of --CO(CH2)2CONH(CH2)3Si(X)3,
--CO(CH2)3CONH(CH2)3Si(X)3 and
--CONH(CH2)3Si(X)3, in which X is ethoxy or methoxy;
X2 is one among the group consisting of --H, --CH3, CH3O--
and halogen; M is the metal ion coordinated with porphyrin ring.

[0070] Another aspect of the present invention provides use of hybrid
lipid compound based on pentaerythritol as light-control materials for
controlling drug release from liposome.

[0071] Another aspect of the present invention provides the use of hybrid
lipid compound based on pentaerythritol, which is used for the
preparation of Nano-composite membrane materials.

[0072] Another aspect of the present invention provides use of hybrid
lipid compound based on pentaerythritol, which is used for the removal of
organic pollutants in the environment.

[0073] To achieve the purpose of the present invention, another aspect of
the present invention provides a hybrid lipid compound based on
pentaerythritol with a constructional formula

##STR00068##

Wherein:

[0074] R1 is C6˜C18 alkyl, R2 is
C6˜C18 alkyl, R3 is one among the group consisting
of CO(CH2)mCONH(CH2)3Si(X)3,
CO(CH2)5N(CH3)2(CH2)3Si(X)3Y or
CONH(CH2)3Si(X)3, in which m is 2 or 3, X is ethoxy or
methoxy, Y is the halogenated group;

[0075] A method for making the above hybrid lipid compound comprises
following steps:

1) forming a compound 1 with a constructional formula

##STR00069##

by reacting alkyl amines and alkyl bromide under heating reflux for 5
days, 2) forming a compound with a constructional formula

##STR00070##

By reacting

##STR00071##

with succinic anhydride or glutaric anhydride through nucleophilic
reaction; then forming a compound with a constructional formula

##STR00072##

by reacting

##STR00073##

with excess 4 to 6 times of pentaerythritol through esterification
reaction; 3) forming a hybrid lipid compound with a constructional
formula

##STR00074##

by reacting the

##STR00075##

with 3-isocyanatopropyltriethoxysilane or
3-isocyanatopropyltrimethoxysilane through nucleophilic reaction for 2-3
days, wherein R3 is --CONH(CH2)3Si(X)3, Or by
reacting

##STR00076##

with 6-Bromohexanoyl chloride through esterification reaction, followed
reacting with dimethylamine gas saturated tetrahydrofuran solution
through nucleophilic reaction, and then reacting with
3-Bromopropyltriethoxysilane or 3-Bromopropyltrimethoxysilane through
nucleophilic reaction, wherein R3 is
--CO(CH2)5N(CH3)2(CH2)3Si(X)3Y. Or by
reacting

##STR00077##

with succinic anhydride or glutaric anhydride through nucleophilic
reaction, following reacting with 3-aminopropyltriethoxysilane or
3-aminopropyltrimethoxysilane through condensation reaction, wherein
R3 is --CO(CH2)mCONH(CH2)3Si(X)3.

[0076] Another aspect of the present invention provides a hybrid lipid
compound based on pentaerythritol with a constructional formula

##STR00078##

Wherein:

[0077] R4 is C6˜C18 alkyl, R5 is one among the
group consisting of CONH(CH2)3Si(X)3,
CO(CH2)mCONH(CH2)3Si(X)3 and
CO(CH2)5N(CH2)2(CH2)3Si(X)3Y, in which
m is 2 or 3, X is ethoxy or methoxy, Y is the halogenated group.

[0078] A method for making the above hybrid lipid compound comprises
following steps:

1) forming a compound with a constructional formula

##STR00079##

by reacting pentaerythritol and 3 times of alkyl bromide with a
constructional formula of R4--Br in alkaline conditions for 6 hours;
2) forming a hybrid lipid compound with a constructional formula

##STR00080##

by reacting

##STR00081##

with 3-Isocyanatopropyltriethoxysilane or
3-Isocyanatopropyltrimethoxysilane for 2-3 days, wherein R5 is
--CONH(CH2)3Si(X)3; or by reacting

##STR00082##

with 6-Bromohexanoyl chloride through esterification reaction, following
reacting with dimethylamine gas saturated tetrahydrofuran solution
through nucleophilic reaction, and then reacting with
3-Bromopropyltriethoxysilane or 3-Bromopropyltrimethoxysilane through
nucleophilic reaction, wherein R5 is
--CO(CH2)5N(CH3)2(CH2)3Si(X)3Y; or by
reacting

##STR00083##

with succinic anhydride or glutaric anhydride through nucleophilic
reaction, following reacting with 3-aminopropyltriethoxysilane or
3-aminopropyltrimethoxysilane through nucleophilic reaction wherein
R5 is --CO(CH2)mCONH(CH2)3Si(X)3.

[0079] A hybrid lipid compound containing azobenzene unit based on
pentaerythritol of the present invention with a constructional formula

##STR00084##

Wherein:

[0080] R1 is C6˜C18 alkyl, R2 is
C6˜C18 alkyl, R1 and R2 can be the same or
different, R3 is OEt or OCH3, a is 2 or 3; b is 2 or 3, c is 1,
and c is 0 when b is 0, X is one among the group consisting of H,
CH3, CH3O, F, Cl, Br and NO2, Y is one among the group
consisting of H, CH3, CH3O, F, Cl and Br, when Y is at the
2-position of amino group, it is H, CH3 or CH3O, when Y is at
the 3-position of amino group, it is H, F, Cl or Br.

[0081] The synthesis route of the present invention is described according
to the following scheme:

##STR00085## ##STR00086##

Wherein, R1 is C6˜C18 alkyl, R2 is
C6˜C18 alkyl, R1 and R2 can be the same or
different, R3 is OEt or OCH3, a is 2 or 3; b is 2 or 3, c is 1,
and c is 0 when b is 0, When R4 is Ph, then R5 is H; When
R4 is CH3, then R5 is CH3; X is one among the group
consisting of H, CH3, CH3O, F, Cl, Br and NO2, Y one among
the group consisting of H, CH3, CH3O, F, Cl and Br; when Y is
at the 2-position of amino group, it is one among H, CH3 and
CH3O, when Y is at the 3-position of amino group, it is one among H,
F, Cl and Br.

[0082] The synthesis of the compound 1 is described in the publication (J.
Am. Chem. Soc. 118, 8524-8530, 1996), the synthesis of the compound 4 is
described in the publication (Chinese organic chemistry, 2005, 9,
1049-1052), the synthesis of the compound 8 is described in the
publication (Journal of Qingdao University of Science and Technology.
2008, 29(2), 110-113).

[0083] The process of the present invention comprises:

(1) In polar organic solvent, by reacting a compound 1 and a compound 2
at 25-70quadrature for 24-48 hours, following washing in turn with
acidic water and water, and recrystalling to obtaine a compound 3. The
molar ratio of the compound 1 to the compound 2 is 1:1.5-4, the preferred
ratio is 1:2-2.5, the said polar organic solvents can be tetrahydrofuran,
acetone, acetonitrile, dimethylformamide, etc. (2) In polar organic
solvent, by reacting the compound 3, DCC, DMAP and a compound 4 at
50-80quadrature for 12-36 hours to obtain a compound 5. The molar
ration of the compound 3, DCC, DMAP and the compound 4 is
1:1-3:0.8-1.2:3-6, the preferred molar ratio is 1:1.5-2:0.9-1.1:4-5, the
said polar organic solvents can be tetrahydrofuran, acetone,
acetonitrile, dimethyl formamide, etc. (3) In aprotic organic solvent, by
reacting the compound 5, DMAP, deacid agent and the compound 2 at
25-70quadrature for 24-48 hours, following washing in turn with acidic
water and water, then purifying by column chromatography to obtain a
compound 6. The molar ratio of the compound 5, DMAP, the deacid agent and
the compound 2 is 1:0.4-1:1-6:2-5, the preferred ratio is
1:0.4-0.6:3-5:3-4, the said aprotic organic solvent can be benzene,
toluene, methylene chloride, chloroform, the deacid agent is
triethylamine or pyridine, etc. (4) In a mixed solvent of tetrahydrofuran
and methanol or ethanol, by reacting the compound 6 and hydrogen in the
presence of the catalyst at 25-80quadrature for 12-48 hours to obtain a
compound 7. The mass ratio of the compound 6 to the catalyst is
1:0.4-0.6, hydrogen pressure is 1.0-1.2 MPa, volume ratio of mixed
solvent of tetrahydrofuran to methanol or ethanol is 3-4:1, the catalyst
is Pd/C or hydroxide palladium/carbon. (5) In aprotic organic solvent, by
reacting the compound 7, DCC and a compound 8 at 25-45quadrature for
24-60 hour to obtain a compound 9. The molar ratio of the compound 7, DCC
and the compound 8 is 1:1.2-1.5:1.1-2. The aprotic organic solvent can be
benzene, toluene, methylene chloride, chloroform and so on. (6) In
aprotic organic solvents, by reacting the compound 9, a compound 10 and
dibutyltin dilaurate at 40-70quadrature for 48-72 hours to obtain a
compound 11. The molar ratio of the compound 9, the compound 10 and
dibutyltin dilaurate is 1:2-4:0.2-0.8, the preferred molar ratio is
1:2-2.5:0.3-0.5, the aprotic organic solvent can be benzene, toluene,
methylene chloride, chloroform, etc. (7) In aprotic organic solvents, by
reacting the compound 9, DMAP, deacid agent and the compound 2 at
25-70quadrature for 24-48 hours, following washing in turn with acidic
water and water, then purifying by column chromatography to obtain a
compound 12. The molar ratio of the compound 9, DMAP, deacid agent and
the compound 2 is 1:0.8-2:3-8:4-8, the preferred molar ratio is
1:1-1.5:5-6:6-7. The aprotic organic solvent can be benzene, toluene,
methylene chloride, chloroform, etc, the deacid agent can be
triethylamine or pyridine, etc. (8) In aprotic organic solvent, by
reacting the compound 12, DCC and a compound 13 at 25-40quadrature for
24-36 hours to obtain a compound 14. The molar ratio of the compound 12,
DCC and the compound 13 is 1:1-2:1.5-2.0. The aprotic organic solvents
can be benzene, toluene, methylene chloride, chloroform, etc.

[0084] A hybrid lipid compound containing cholesterol unit based on
pentaerythritol of the present invention with a constructional formula

##STR00087##

Wherein:

[0085] R1 is C6˜C18 alkyl, R2 is
C6˜C18 alkyl, R1 and R2 can be the same or
different, R3 is OEt or OCH3, a is 2 or 3; b is 2 or 3, c is 1,
and c is 0 when b is 0.

[0086] The synthesis route of the present invention is described according
to the following scheme:

##STR00088## ##STR00089##

wherein R1 is C6˜C18 alkyl, R2 is
C6˜C18 alkyl, R1, R2 can be the same or
different, R3 is OEt or OCH3, a is 2 or 3; b is 2 or 3, c is 1,
and c is 0 when b is 0.

[0087] The synthesis of the compound 1 is described in the applied patent
application (application number: 200910073423.5), the synthesis of the
compound 2 is described in the publication (Carbohydrate Polymers 2006,
65, 337-345; European Polymer Journal 2008, 44, 55-565).

[0088] The process of the present invention comprises:

(1) In the polar organic solvent, by reacting a compound 1, DCC, DMAP and
a compound 2 at 50-80quadrature for 12-36 hours to obtain a compound 3.
The molar ratio of the compound 1, DCC, DMAP and the compound 2 is
1:1-3:0.8-1.2:1-3, the preferred molar ratio is 1:1.5-2:0.9-1.1:1.2-2.5.
The polar organic solvents can be tetrahydrofuran, acetone, acetonitrile,
dimethyl formamide, etc. (2) in a mixed solvent of tetrahydrofuran and
methanol or ethanol, by reacting the compound 3, hydrogen in the presence
of catalyst at 25-80quadrature for 12-48 hours to obtain a compound 4.
The mass ratio of the compound 3 to the catalyst is 1:0.4-0.6, hydrogen
pressure is 1.0-1.2 MPa, the volume ratio of mixed solvent of
tetrahydrofuran and methanol or ethanol is 3-4:1, the catalyst is Pd/C or
hydroxide palladium/carbon. (3) In aprotic organic solvent, by reacting
the compound 4, a compound 5 and dibutyltin dilaurate at
40-70quadrature for 48-72 hours to obtain a compound 6. The molar ratio
of the compound 4, the compound 5 and dibutyltin dilaurate is
1:2-4:0.2-0.8, the preferred molar ratio is 1:2-2.5:0.3-0.5, the aprotic
organic solvent can be benzene, toluene, methylene chloride, chloroform,
etc. (4) In aprotic organic solvent, by reacting the compound 4, DMAP,
deacid agent and a compound 7 at 25-70 for 24-48 hours, following washing
in turn with acidic water and water, then purifying by column
chromatography to obtain a compound 8. The molar ratio of the compound 4,
DMAP, deacid agent and the compound 7 is 1:0.8-2:3-8:4-8, the preferred
molar ratio is 1:1-1.5:5-6:6-7. The aprotic organic solvent can be
benzene, toluene, methylene chloride, chloroform, etc, the deacid agent
can be triethylamine or pyridine, etc. (5) In aprotic organic solvent, by
reacting the compound 8, DCC and a compound 9 at 25-40 for 24-36 hours to
obtain a compound 10. The molar ratio of the compound 8, DCC and the
compound 9 is 1:1-2:2.0-2.5. The aprotic organic solvent can be benzene,
toluene, methylene chloride, chloroform, etc.

[0089] A hybrid lipid compound containing porphyrin unit based on
pentaerythritol of the present invention with a constructional formula

##STR00090##

Wherein:

[0090] R1 is C6˜C18 alkyl, R2 is
C6˜C18 alkyl, R1 and R2 can be the same or
different, R3 is OEt or OCH3, a is 2 or 3; b is 2 or 3, c is 1,
and c is 0 when b is 0, X is one among the group consisting of H,
CH3, CH3O, halogen, M represents two hydrogen or all the metals
ion coordinated with porphyrin ring, such as iron (Fe), Zinc (Zn),
Magnesium (Mg), Manganese (Mn), Cobalt (Co), Copper (Cu), Molybdenum
(Mo), Chromium (Cr), Gadolinium (Gd), Iridium (Ir).

[0091] The synthesis route of the present invention is described according
to the following scheme:

##STR00091## ##STR00092##

Wherein, R1 is C6˜C18 alkyl, R2 is
C6˜C18 alkyl, R1 and R2 can be the same or
different, R3 is OEt or OCH3, a is 2 or 3; b is 2 or 3, c is 1,
and c is 0 when b is 0, X is one among the group consisting of H,
CH3, CH3O, halogen, M represents two hydrogen or all the metals
ion coordinated with porphyrin ring, such as iron (Fe), Zinc (Zn),
Magnesium (Mg), Manganese (Mn), Cobalt (Co), Copper (Cu), Molybdenum
(Mo), Chromium (Cr), Gadolinium (Gd), Iridium (Ir). Y is the anion formed
metal salts with M, the anion is halogen anion or acetate ions.

[0092] The synthesis method of the compound 1 is described in the applied
patent application (application number: 200910073423.5), the synthesis
method of the compound 2 is described in the publication (Chemical
Reagents, 1994, 16(2), 105˜106; Tetrahedron 2004, 60, 2757-2763).

[0093] The process of the present invention comprises:

(1) In aprotic organic solvent, by reacting a compound 1, DCC and a
compound 2 at 25-45quadrature for 24-72 hours to yield a compound 3.
The molar ratio of the compound 1, DCC and the compound 2 is
1:1.2-1.5:1.1-2. The aprotic organic solvents can be benzene, toluene,
methylene chloride, chloroform, DMSO or DMF, etc. (2) In aprotic organic
solvent, by reacting the compound 3, a compound 4 and dibutyltin
dilaurate at 40-80quadrature for 36-72 hours to afford a compound 5.
The molar ratio of the compound 3, the compound 4 and dibutyltin
dilaurate is 1:2-5:0.2-1.0, the preferred molar ratio is 1:2-3:0.3-0.6.
The aprotic organic solvents can be benzene, toluene, methylene chloride,
chloroform, etc. (3) In aprotic organic solvent, by reacting the compound
3, DMAP, deacid agent and a compound 6 at 25-75quadrature for 24-48
hours, following washing in turn with acidic water and water, then
purifying by column chromatography to afford a compound 7. The molar
ratio of the compound 3, DMAP, the deacid agent and the compound 6 is
1:0.8-2:3-9:3-10, the preferred molar ratio is 1:1-1.5:5-6:5-8. The
aprotic organic solvent can be benzene, toluene, methylene chloride,
chloroform, the deacid agent can be triethylamine orpyridine, etc. (4) In
aprotic organic solvent, by reacting the compound 7, DCC and a compound 8
at 25-45quadrature for 24-48 hours to yield a compound 9. The molar
ratio of the compound 7, DCC and the compound 8 is 1:1-2:1.5-2.0. The
aprotic organic solvents can be benzene, toluene, methylene chloride,
chloroform and so on. (5) In organic solvent, by reacting the compound 5
or the compound 9 with a compound 10 at 25-180quadrature for 2-48
hours, then removing reaction solvent in vacuum and washing with water,
the crude product was purified by column chromatography to afford a
compound 11. The molar ratio of the compound 5 or the compound 9 to the
compound 10 is 1:5-25, the preferred molar ratio is 1:10-15, the
preferred temperature is the boiling point of the corresponding organic
solvent. The organic solvent can be DMSO, DMF, methanol, ethanol,
dichloromethane, chloroform, etc.

[0094] A hybrid lipid containing benzene unit based on pentaerythritol of
the present invention with a constructional formula

##STR00093##

Wherein:

[0095] R1 is C6˜C18 alkyl, R2 is
C6˜C18 alkyl, R1 and R2 can be the same or
different, R3 is OEt or OCH3, a is 2 or 3; b is 2 or 3, c is 1,
and c is 0 when b is 0, X is one among the group consisting of H,
CH3, CH3O, halogen and NO2.

[0096] The synthesis of the hybrid lipid in the present invention is
described according to the following scheme:

##STR00094##

[0097] A hybrid lipid containing carboxyl unit based on pentaerythritol of
the present invention with a constructional formula

##STR00095##

Wherein:

[0098] R1 is C6˜C18 alkyl, R2 is
C6˜C18 alkyl, R1 and R2 can be the same or
different, R3 is OEt or OCH3, a is 2 or 3; b is 2 or 3, c is 1,
and c is 0 when b is 0, d is 2 or 3.

[0099] The synthesis of the hybrid lipid compound in present invention is
described according to the following scheme:

##STR00096##

[0100] The synthesis of the compound 1 is described in the publication (J.
Am. Chem. Soc. 118, 8524-8530, 1996), the synthesis of the compound 4 is
described in the publication (Chinese organic chemistry, 2005, 9,
1049-1052).

[0101] The process of the present invention comprises:

(1) In polar organic solvent, by reacting a compound 1 and a compound 2
at 25-70quadrature for 24-48 hours, following washing in turn with
acidic water and water, and then recrystallizing to obtaine a compound 3.
The molar ratio of the compound 1 and the compound 2 is 1:1.5-4, the
preferred molar ratio is 1:2-2.5. The polar organic solvent can be
tetrahydrofuran, acetone, acetonitrile and dimethyl formamide, etc. (2)
In polar organic solvent, by reacting the compound 3, DCC, DMAP and a
compound 4 at 50-80quadrature for 12-36 hours to afford a compound 5.
The molar ratio of the compound 3, DCC, DMAP and the compound 4 is
1:1-3:0.8-1.2:3-6, the preferred molar ratio is 1:1.5-2:0.9-1.1:4-5. The
polar organic solvents can be tetrahydrofuran, acetone, acetonitrile,
dimethyl formamide, etc. (3) In aprotic organic solvent, by reacting the
compound 5, a compound 6 and dibutyltin dilaurate at 40-70quadrature
for 48-72 hours to obtain a compound 7. The molar ratio of the compound
5, the compound 6 and dibutyltin dilaurate is 1:1-2:0.2-0.8, the
preferred molar ratio is 1:1-1.25:0.3-0.5. The aprotic organic solvents
can be benzene, toluene, methylene chloride, chloroform and so on. (4) In
aprotic organic solvent, by reacting the compound 5, DMAP, deacid agent
and a compound 8 at 25-70quadrature for 24-48 hours, following washing
in turn with acidic water and water, and later purifying by column
chromatography to afford a compound 9. The molar ratio of the compound 5,
DMAP, deacid agent and the compound 8 is 1:0.4-1:1-6:2-5, the preferred
molar ratio is 1:0.4-0.6:3-5:3-4. The aprotic organic solvents can be one
among benzene, toluene, methylene chloride, chloroform, the deacid agent
can be triethylamine or pyridine, etc. (5) In aprotic organic solvent, by
reacting the compound 9, DCC and a compound 10 at 25-40quadrature for
24-36 hours to afford a compound 11. The molar ratio of the compound 9,
DCC and the compound 10 is 1:1-2:1.1-1.5. The aprotic organic solvent can
be benzene, toluene, methylene chloride, chloroform and so on. (6) In
mixed solvent of tetrahydrofuran and methanol or ethanol, by reacting the
compound 9, hydrogen in the presence of catalyst at 25-80quadrature for
12-48 hours to yield a compound 12. The mass ratio of the compound 9 and
the catalyst is 1:0.4-0.6, hydrogen pressure is 1.0-1.2 MPa, the volume
ratio of mixed solvent of tetrahydrofuran and methanol or ethanol is
3-4:1, catalyst is Pd/C or hydroxide palladium/carbon. (7) In aprotic
organic solvent, by reacting the compound 12, DCC and a compound 10 at
25-40quadrature for 24-36 hours to afford a compound 13. The molar
ratio of the compound 12, DCC and the compound 10 is 1:1-2:1.1-1.5. The
aprotic organic solvent can be benzene, toluene, methylene chloride,
chloroform and so on. (8) In the aprotic organic solvent, by reacting the
compound 13, DMAP, deacid agent and a compound 14 at 25-70quadrature
for 24-48 hours, following washing in turn with acidic water and water,
and later purifying by column chromatography to afford a compound 15. The
molar ratio of the compound 13, DMAP, deacid agent and the compound 14 is
1:0.4-1:1-6:4-8, the preferred molar ratio is 1:0.4-0.6:3-5:5-7. The
aprotic organic solvents can be benzene, toluene, methylene chloride,
chloroform, the deacid agent can be triethylamine or pyridine, etc.

[0102] Hybrid Lipid compounds of the present invention show the following
advantages:

1. Hybrid Lipid compounds of the present invention can form the liposomes
(also known as cerasome) by hydrolysis and condensation, which having the
uniform size, silicate network surface, high stability. When surfactant
Triton X-100 (TX-100) was added to the cerasome solution, size changes of
cerasome was tested, and conventional liposomes made from phospholipids
(DSPC) which were used as control under the same conditions is compared
to examine the stability of the cerasome, when 30 times amount of TX-100
solution were added, sizes of cerasome derived from the hybrid lipid of
the present invention remained unchanged, while traditional liposomes
from the DSPC decrease their sizes obviously in the presence of 5 times
amount of TX-100, which indicating vesicle structure has been destroyed,
so that it provides a strong evidence that cerasome derived from hybrid
lipid compounds of the present invention shows higher stability than the
conventional liposomes. 2. Hybrid lipid compounds of the present
invention can form liposome (also known as cerasome) by hydrolysis and
condensation reaction, the cerasomes derived from the hybrid lipid
compounds can interact with the encapsulated hydrophobic or hydrophilic
drugs via electronic conjugated attraction or electrostatic attraction,
thereby enhancing drug encapsulation efficiency, encapsulation rate can
reach 95.4%˜99.0%. 3. Cerasomes derived from the hybrid lipid
compounds of the present invention have the surface of silicate network
structure, leakage of drugs is not easy. 4. The process and preparation
method of the present invention is simple, raw materials are cheap,
reaction conditions are mild, with strong operational and promoting the
clinical application and industrial production. 5. Cerasomes with
silicate framework derived from the hybrid lipid compounds of the present
invention is more stable than the existing liposomes, and can be used as
carriers of the various types of drugs, dyes, quantum dots, magnetic
nanoparticles and DNA, which showing a good prospect.

(1) presents the Changes in particle size of cerasome in the presence of
different times of Surfactant TX-100; (2) presents the Changes in
particle size of liposome prepared from DSPC in the presence of different
times of Surfactant TX-100;

(1) presents the UV-visible absorption spectra of the Chloroform solution
of compound 45 in embodiment 43, (2) presents the UV-visible absorption
spectra of the cerasome in embodiment 46;

[0118] FIG. 16 is the Particle size distribution of cerasome in the
presence of different times of TX-100, wherein:

(1) presents the Changes in particle size of cerasome in embodiment 46 in
the presence of different times of Surfactant TX-100; (2) presents the
Changes in particle size of liposome prepared from DSPC in embodiment 46
in the presence of different times of Surfactant TX-100;

[0121] The following specific examples will help to understand the present
invention, but do not limit the content of the present invention.

Example 1

[0122] The hybrid lipid compound based on pentaerythritol in this
embodiment with a constructional formula

##STR00097##

Wherein:

[0123] R1 is C6˜C18 alkyl, R2 is
C6˜C18 alkyl, R5 is one among the group consisting
of --CO(CH2)5N(CH3)2(CH2)3Si(X)3Y,
--CO(CH2)2CONH(CH2)3Si(X)3,
--CO(CH2)3CONH(CH2)3Si(X)3 and
--CONH(CH2)3Si(X)3, in which X is ethoxy or methoxy, Y is
the halogenated group; a is 2 or 3.

[0124] The liposomes prepared from the hybrid lipid compound in this
embodiment have uniform size, silicate network surface and higher
stability. When surfactant Triton X-100 (TX-100) was added to the
liposomes solution, size changes of liposomes was tested, and
conventional liposomes made from phospholipids (DSPC) which were used as
control under the same conditions were compared to examine the stability
of the cerasome. When 30 times amount of TX-100 solution were added,
sizes of liposomes (cerasome) derived from the hybrid lipid of the
present invention remained unchanged, while traditional liposomes from
the DSPC decrease their sizes obviously in the presence of 5 times amount
of TX-100, which indicating vesicle structure has been destroyed, so that
it provides a strong evidence that cerasomes derived from hybrid lipid of
the present invention show higher stability than the conventional
liposomes. The encapsulation rate of the cerasome prepared from the lipid
of this embodiment is 95.4%˜98.7%.

Example 2

[0125] The difference between the present embodiment with the embodiment 1
is that the said halogenated group in the present embodiment is Cl, Br or
I. Other description is the same as embodiment 1.

Example 3

[0126] The difference between the present embodiment with the embodiment 1
or embodiment 2 is that the said R1 in the present embodiment is
hexyl, octyl, undecyl, dodecyl, tridecyl, tetradecyl, fifteen alkyl,
hexadecyl, seventeen alkyl or octadecyl. Other description is the same as
embodiment 1 and embodiment 2.

Example 4

[0127] The difference between the present embodiment with the embodiment 1
or embodiment 2 or embodiment 3 is that the said R2 in the present
embodiment is hexyl, octyl, undecyl, dodecyl, tridecyl, tetradecyl,
fifteen alkyl, hexadecyl, seventeen alkyl or octadecyl. Other description
is the same as embodiment 1 and embodiment 2 and embodiment 3.

Example 5

[0128] A method for making the hybrid lipid compound in embodiment 1
comprises following steps:

[0129] 1) forming a compound 1 with a constructional formula

##STR00098##

by reacting alkyl amines and alkyl bromide under heating reflux through
substitution reaction for 5 days, wherein the alkyl amines is
R1--NH2 and the alkyl bromide is R2--Br, in which R1
is C6˜C18 alkyl and R2 is C6˜C18
alkyl;

[0130] 2) forming a compound 2 with a constructional formula

##STR00099##

by reacting the compound 1 with succinic anhydride or glutaric anhydride
through nucleophilic reaction, wherein a is 2 or 3;

[0131] then forming a compound 3 with a constructional formula

##STR00100##

by reacting the compound 2 with excess 4 to 6 times of pentaerythritol
through esterification reaction, wherein a is 2 or 3;

by reacting the compound 3 with 3-isocyanatopropyltriethoxysilane or
3-isocyanatopropyltrimethoxysilane through nucleophilic reaction, wherein
R51 is --CONH(CH2)3Si(X)3, in which X is ethoxy or
methoxy;

[0133] or forming a hybrid lipid with a constructional formula

##STR00102##

by reacting the compound 3 with 6-Bromohexanoyl chloride through
esterification reaction, following reacting with dimethylamine gas
saturated tetrahydrofuran solution through nucleophilic reaction, and
then reacting with 3-Bromopropyltriethoxysilane or
3-Bromopropyltrimethoxysilane through nucleophilic reaction, wherein
R52 is
--CO(CH2)5N(CH3)2(CH2)3Si(X)3Y, in
which X is ethoxy or methoxy and Y is halogenated group;

[0134] or forming a hybrid lipid compound with a constructional formula

##STR00103##

by reacting the compound 3 with succinic anhydride or glutaric anhydride
through nucleophilic reaction, following reacting with
3-aminopropyltriethoxysilane or 3-aminopropyltrimethoxysilane through
condensation reaction, and then dehydrating, wherein R53 is
--CO(CH2)2CONH(CH2)3Si(X)3 or
--CO(CH2)3CONH(CH2)3Si(X)3, in which X is ethoxy
or methoxy.

Example 6

[0135] A method for making the hybrid lipid compound with a following
constructional formula comprises following steps:

##STR00104##

wherein R1 is C6˜C18 alkyl, R2 is
C6˜C18 alkyl, R1 and R2 is the same, a is 2 or
3, R511 is --CONH(CH2)3Si(X)3, in which X is ethoxy
or methoxy.

[0136] 1) forming a compound 1 with a constructional formula

##STR00105##

by reacting alkyl amines and alkyl bromide with the molar ratio of 1:2
under the catalysis of potassium carbonate in a heating reflux ethanol
solvent, for 5 days at 95quadrature;

[0137] 2) forming a compound 2 with a constructional formula

##STR00106##

In the tetrahydrofuran solvent, by reacting the compound 1 with succinic
anhydride or glutaric anhydride with the molar ratio of 1:1.2 for 2 days
at room temperature;

[0138] then forming a compound 3 with a constructional formula

##STR00107##

by reacting the compound 2 with excess 4 to 6 times of pentaerythritol
with dicyclohexyl carbodiimide (DCC) as condensing agent and
4-dimethylamino pyridine (DMAP) as catalyst at 40quadrature for 1 day
in dimethyl sulfoxide (DMSO) or dimethylformamide (DMF);

[0139] 3) forming a hybrid lipid with a constructional formula

##STR00108##

by reacting

##STR00109##

with 3-Isocyanatopropyltriethoxysilane or
3-Isocyanatopropyltrimethoxysilane with the molar ratio of 1:3 in
chloroform or methylene chloride solvent for 2-3 days at 50quadrature,
wherein R511 is --CONH(CH2)3Si(X)3, a is 2 or 3, the
synthetic route is illustrated in Scheme I

##STR00110##

wherein, L in scheme quadrature is a leaving group.

Example 7

[0140] The difference between the present embodiment with the embodiment 6
is that R1 and R2 is different in present embodiment, and

##STR00111##

is formed by reacting alkyl amines R1--NH2 and alkyl bromide
Z--R2 with the molar ratio of 1:2 under the catalysis of potassium
carbonate for 5 days at 95quadrature in a refluxing ethanol solvent,
wherein Z is bromide group, and other description is the same as the
embodiment 6.

Example 8

[0141] A method for preparing a hybrid lipid compound with a following
constructional formula is as follows:

##STR00112##

wherein R1 is C6˜C18 alkyl, R2 is
C6˜C18 alkyl, R521 is
--CO(CH2)8N(CH3)2(CH2)3Si(X)3Y, in
which X is ethoxy or methoxy, Y is Cl, Br or I;

[0142] by reacting the compound 3 with a constructional formula

##STR00113##

with 6-Bromohexanoyl chloride by esterification reaction with the molar
ratio of 1:3.5, following reacting with dimethylamine gas saturated
tetrahydrofuran solution through nucleophilic reaction, and then reacting
with 3-Bromine propyltriethoxysilane or 3-Bromopropyltrimethoxysilane by
nucleophilic reaction with the molar ratio of 1:4 in chloroform or
methylene chloride solvent under the catalysis of, organic base (such as
triethylamine, pyridine or DMAP) wherein R521 is
--CO(CH2)5N(CH3)2(CH2)3Si(X)3Y, and
the compound in the present embodiment with a constructional formula

##STR00114##

was prepared according to the embodiment 6 or the embodiment 7.

Example 9

[0143] A method for preparing a hybrid lipid compound with a following
constructional formula is as follows:

##STR00115##

wherein R1 is C6˜C18 alkyl, R2 is
C6˜C18 alkyl, R531 is
CO(CH2)aCONH(CH2)3SKX)3, in which a is 2 or 3:

[0144] by reacting a compound with a constructional formula

##STR00116##

with succinic anhydride or glutaric anhydride through nucleophilic
reaction with the molar ratio of 1:6, following reacting with
3-aminopropyltriethoxysilane or 3-aminopropyltrimethoxysilane through
nucleophilic reaction under the catalysis of DCC or EDC at room
temperature for 24 h, wherein R531 is one among the group consisting
of CO(CH2)aCONH(CH2)3Si(X)3, and the compound in
the present embodiment with a constructional formula

##STR00117##

was prepared according to the embodiment 6 or the embodiment 7.

Example 10

[0145] A method for preparing a hybrid lipid compound based on
pentaerythritol with the formula of
C71H144N4O18Si3 is as follows:

[0146] Put the solution of a compound with a constructional formula

##STR00118##

(0.24 g, 0.35 mmol) in dry dichloromethane into a 100 mL two necked,
round bottomed flask, then add 3-isocyanatopropyltriethoxysilane (0.26 g,
1.05 mmol) and Dibutyltin dilaurate (0.069 g, 0.105 mmol); the reaction
mixture was stirred at 40quadrature for 48 h under nitrogen atmosphere.
After completion, the solution was concentrated under vacuum and the
residue was purified with a silica gel column to give a hybrid lipid
based on pentaerythritol (colorless oil), the yield is 32%.

[0150] Put 2 mg hybrid lipid based on pentaerythritol in this embodiment
compound with a constructional formula
C71H144N4O15Si3 into a 20 mL round bottom flask,
add 5 mL chloroform to dissolve the compound and then slowly distill to
form thin films in the flask wall in vacuum, dry at 35quadrature in
vacuum oven to completely remove the chloroform, water of different pH
was then added to the flask with thin films to reach the solution
concentration of 0.5 mmol/L. Such mixture was ultrasonified for 5 minutes
to get a certain turbidity of the solution, the resultant solution was
placed at room temperature for 12 hours to obtain aqueous solution of
cerasome 1. The size and morphology was later detected by DLS and TEM
instruments. Specific transmission electron microscopy is shown in FIG.
1, and the particle size is shown in FIG. 2 and Table 1.

[0151] FIG. 1 indicates that particle size of the cerasome prepared by the
hybrid lipid compound in this embodiment is about 150 nm. FIG. 2 and
Table 1 show the average particle size of the cerasome is 143 nm, which
with narrow particle size distribution, and polydispersity index of
0.237.

[0152] The hybrid lipid compound based on pentaerythritol in this
embodiment, with a constructional formula

##STR00120##

Wherein:

[0153] R4 is C6˜C18 alkyl, R5 is one among the
group consisting of CON H(CH2)3Si(X)3,
CO(CH2)aCONH(CH2)3Si(X)3 or
CO(CH2)5N(CH3)2(CH2)3Si(X)3Y, in which
a is 2 or 3, X is hydrolyzable group which can be ethoxy or methoxy, Y is
the halogenated group.

[0154] The liposomes prepared from hybrid lipid compound in this
embodiment have uniform size, the silicate network surface and higher
stability; When surfactant Triton X-100 (TX-100) was added to the
liposome solution, size changes of liposome was tested, and conventional
liposomes made from phospholipids (DSPC) which were used as control under
the same conditions was compared to examine the stability of the
cerasome, when 30 times amount of TX-100 solution were added, sizes of
liposomes (cerasome) derived from the hybrid lipid of the present
invention remained unchanged, while traditional liposomes from the DSPC
decrease their sizes obviously in the presence of 5 times amount of
TX-100, which indicating vesicle structure has been destroyed, so that it
provides a strong evidence that cerasome derived from hybrid lipid
compound of the present invention shows higher stability than the
conventional liposomes. The encapsulation rate of the cerasome prepared
from the hybird lipid compound of this embodiment is 95.4%˜98.7%.

Example 12

[0155] The difference between the present embodiment with the embodiment
11 is that the described halogen in present embodiment can be one among
the group of Cl, Br or I. Other description is the same as the embodiment
11.

Example 13

[0156] The difference between the present embodiment with the embodiment
11 or embodiment 12 is that the described R4 in present embodiment
can be one among the group of hexyl, octyl, undecyl, dodecyl, tridecyl,
tetradecyl, fifteen alkyl, hexadecyl, seventeen alkyl and octadecyl.
Other description is the same as the embodiment 11 and the embodiment 12.

Example 14

[0157] The hybrid lipid compound based on pentaerythritol in this
embodiment with a constructional formula

##STR00121##

wherein: R4 is C6˜C18 alkyl, R5 is one among
the group consisting of CONH(CH2)3Si(X)3,
CO(CH2)aCONH(CH2)3Si(X)3 or
CO(CH2)5N(CH3)2(CH2)3Si(X)3Y, in which
a is 2 or 3, X is hydrolyzable group which can be ethoxy or methoxy, Y is
the halogenated group.

[0158] A method for preparing the above hybrid lipid compound comprises
following steps:

[0159] 1) forming a compound with a constructional formula

##STR00122##

by reacting pentaerythritol and 3 times excess amount of alkyl bromide
with a constructional formula R4--Br in alkaline conditions through
the nucleophilic substitution reaction for 6 hours, wherein R4 is
C6˜C18 alkyl;

[0160] 2) forming a hybrid lipid with a constructional formula

##STR00123##

by reacting a compound with a constructional formula

##STR00124##

with 3-Isocyanatopropyltriethoxysilane or
3-Isocyanatopropyltrimethoxysilane through nucleophilic reaction for 2-3
days, wherein R51 is --CONH(CH2)3Si(X)3,

[0161] or by reacting a compound with a constructional formula

##STR00125##

with 6-Bromohexanoyl chloride by esterification reaction, following
reacting with dimethylamine gas saturated tetrahydrofuran solution
through nucleophilic reaction, and then reacting with
3-Bromopropyltriethoxysilane or 3-Bromopropyltrimethoxysilane through
nucleophilic reaction to yield a hybrid lipid compound with a
constructional formula

##STR00126##

wherein R52 is
--CO(CH2)5N(CH3)2(CH2)3Si(X)3Y;

[0162] or by reacting a compound with a constructional formula

##STR00127##

with succinic anhydride or glutaric anhydride through nucleophilic
reaction, following reacting with 3-aminopropyltriethoxysilane or
3-aminopropyltrimethoxysilane through nucleophilic reaction to yield a
hybrid lipid compound with a constructional formula

##STR00128##

wherein R53 is --CO(CH2)aCONH(CH2)3Si(X)3,
R4 is C6˜C18 alkyl; in which X is hydrolyzable group
which can be ethoxy or methoxy, Y is the halogenated group, a is 2 or 3.

Example 15

[0163] The hybrid lipid compound based on pentaerythritol in this
embodiment with a constructional formula

##STR00129##

wherein: R4 is C6˜C18 alkyl, R51 is
CONH(CH2)3Si(X)3, in which X is ethoxy or methoxy.

[0164] A method for preparing the above hybrid lipid compound comprises
following steps:

[0165] 1) forming a compound with a constructional formula

##STR00130##

by reacting pentaerythritol and 3 times excess amount of alkyl bromide
with a constructional formula R4--Br through the nucleophilic
substitution reaction for 6 hours;

[0166] 2) forming a hybrid lipid with a constructional formula

##STR00131##

in chloroform or Dichloromethane solvent, by reacting a compound with a
constructional formula

##STR00132##

with 3-Isocyanatopropyltriethoxysilane or
3-Isocyanatopropyltrimethoxysilane with the molar ratio of 1:1 under the
catalysis of Dibutyltin laurate at 50quadrature for 2-3 days, wherein
R51 is --CONH(CH2)3Si(X)3.

[0167] The synthetic route of the hybrid lipid compound based on
pentaerythritol is illustrated in Scheme II

##STR00133##

wherein, L in scheme II is a leaving group.

Example 16

[0168] The hybrid lipid compound based on pentaerythritol in this
embodiment with a constructional formula

##STR00134##

wherein: R4 is C6˜C18 alkyl, R52 is
CO(CH2)5N(CH3)2(CH2)3Si(X)3Y, in which
X is ethoxy or methoxy, Y is Cl, Br or I.

[0169] A method for preparing the above hybrid lipid compound is as
follows:

[0170] In chloroform or dichloromethane solvent, by reacting a compound
with a constructional formula

##STR00135##

with 6-Bromohexanoyl chloride by esterification reaction with the molar
ratio of 1:1.5 under the catalysis of organic base (such as
triethylamine, pyridine or DMAP), following reacting with dimethylamine
gas saturated tetrahydrofuran solution through nucleophilic reaction, and
then reacting with 3-Bromopropyltriethoxysilane or
3-Bromopropyltrimethoxysilane with the molar ratio of 1:4 through
nucleophilic reaction to yield a compound with a constructional formula

##STR00136##

wherein R52 is
--CO(CH2)5N(CH3)2(CH2)3Si(X)3Y, the
compound in the present embodiment with a constructional formula

##STR00137##

was prepared according to the embodiment 15.

Example 17

[0171] The hybrid lipid based on pentaerythritol in this embodiment with a
constructional formula

##STR00138##

wherein: R4 is C6˜C18 alkyl, R53 is
CO(CH2)aCONH(CH2)3Si(X)3, in which a is 2 or 3,
X is ethoxy or methoxy.

[0172] A method for preparing the above hybrid lipid compound is as
follows:

by reacting a compound with a constructional formula

##STR00139##

with succinic anhydride or glutaric anhydride through nucleophilic
reaction with the molar ratio of 1:2, following reacting with
3-aminopropyltriethoxysilane or 3-aminopropyltrimethoxysilane with the
molar ratio of 1:1.5 through nucleophilic reaction under the catalysis of
DCC or EDC at room temperature for 24 hours to yield a hybrid lipid
compound with a constructional formula

##STR00140##

wherein R53 is CO(CH2)aCONH(CH2)3Si(X)3,
the compound in the present embodiment with a constructional formula

##STR00141##

was prepared according to the embodiment 15.

Example 18

[0173] A method for preparing a hybrid lipid based on pentaerythritol with
a constructional formula C63H129NO8Si is as follows:

[0174] Put the solution of a compound with a constructional formula

##STR00142##

(0.25 g, 0.31 mmol) in dry dichloromethane (20 mL), then add
3-Isocyanatopropyltriethoxysilane (0.073 g, 0.31 mmol) and dibutyltin
laurate (0.039 g, 0.062 mmol) under nitrogen atmosphere, and later the
above mixture was heated in 50quadrature oil bath for 48 hours, then
the solution was concentrated under vacuum and the residue was purified
with a silica gel column to give the hybrid lipid compound based on
pentaerythritol, the yield is 81%.

[0177] The preparation method of the cerasome from the hybrid lipid based
on pentaerythritol in this present embodiment was the same as the
embodiment 2, The transmittance electron images of cerasome 2 is
illustrate in FIG. 3, and size distribution is showed in FIG. 4 and table
2.

[0178] FIG. 3 indicates that particle size of the cerasome 2 prepared from
the hybrid lipid in this embodiments is about 200 nm. FIG. 4 and Table 2
shows the average particle size of the cerasome is 196 nm, which with
narrow particle size distribution, and polydispersity index of 0.243.

[0179] A method for preparing a hybrid lipid compound based on
pentaerythritol with a constructional formula C66H133NO9Si
is as follows:

[0180] Step 1: To the solution of a compound with a constructional formula

##STR00144##

(0.17 g, 0.21 mmol) and succinic anhydride (0.042 g, 0.42 mmol) in
dichloromethane (20 mL) was added DMAP (0.028 g, 0.21 mmol) and triethyl
amine (0.084 g, 0.84 mmol). The reaction mixture was warmed to
30quadrature and stirred at this temperature for 5 d. The reaction
solution was then concentrated under vacuum and the residue was purified
by column chromatography to give a white solid compound based on
pentaerythritol with a constructional formula C57H112O7,
the yield is 70%.

[0183] Step 2: To the solution of compound with a constructional formula

##STR00146##

(0.255 g, 0.28 mmol) in dry dichloromethane (20 mL) was added DDC (0.069
g, 0.336 mmol). After 15 min of stirring at room temperature,
3-aminopropyltriethoxysilane (0.093 g, 0.42 mmol) was then added to the
solution and the mixture was stirred for 1 d at room temperature. Then
the solution was concentrated under vacuum and the residue was purified
with a silica gel column to give the hybrid lipid compound based on
pentaerythritol (white solid), the yield is 50%.

[0187] The preparation method of the cerasome 3 from the hybrid lipid
compound based on pentaerythritol with a constructional formula
C66H133NO9Si in this present embodiment was the same as
the embodiment 10. The transmittance electron image of cerasome 3 is
illustrated in FIG. 5, and size distribution is shown in FIG. 6 and table
3.

[0188] FIG. 5 indicates that particle size of the cerasome prepared from
the hybrid lipid compound in this embodiment is about 200 nm. FIG. 6 and
Table 3 shows the average particle size of the cerasome is 216 nm, which
with narrow particle size distribution and polydispersity index of 0.222.

[0189] Cerasomes 1, 2 and 3 was prepared from the corresponding hybrid
lipid compound with a constructional formula
C71H144N4O18S13, C63H129NO8Si and
C66H133NO9Si. When surfactant Triton X-100 (TX-100) was
added to the above cerasome solution, size changes of cerasome was
tested, and conventional liposomes made from phospholipids (DSPC) which
were used as control under the same conditions are compared to examine
the stability of the cerasome, the result is shown in table 4. When 30
times amount of TX-100 solution were added, sizes of cerasome derived
from the hybrid lipid remained unchanged, while traditional liposomes
from the DSPC decrease their sizes obviously in the presence of 5 times
amount of TX-100, which indicating vesicle structure has been destroyed,
so that it provides a strong evidence that cerasomes derived from hybrid
lipid of the present invention show higher stability than the
conventional liposomes, Stability evaluated result of cerasome is
illustrated in table 4.

[0190] A method for preparing a hybrid lipid compound based on
pentaerythritol with a constructional formula
C70H144NO8Si+Br is as follows:

[0191] Step 1: To the solution of a compound with a constructional formula

##STR00148##

(0.65 g, 0.80 mmol) in dichloromethane (20 mL) was added DMAP (0.10 g,
0.8 mmol) and triethyl amine (0.162 g, 1.6 mmol). The reaction mixture
was cooling to 0quadrature and then dichloromethane solvent (8 mL) with
6-Bromohexanoyl chloride (0.27 g, 1.2 mmol) was added dropwise to the
solution and stirred at this temperature for 1 hour, later was stirred at
room temperature for another 16 hours. The reaction solution was then
concentrated under vacuum and the residue was purified by column
chromatography to give a colorless oil compound based on pentaerythritol
with a constructional formula C55H117BrO5, the yield is
56%.

[0194] Step 2: To the solution of a compound with a constructional formula

##STR00150##

(0.45 g, 0.46 mmol) in the dimethylamine saturated THF solution (40 mL)
and the mixture was subsequently stirred at room temperature for 3 days.
Then air was bubbled into the mixture in order to remove excess
dimethylamine. The solvent was evaporated in vacuo and the residual solid
was dissolved in chloroform (20 mL). The solution was then washed in turn
with saturated aqueous sodium chloride, 4% aqueous sodium hydrogen
carbonate. After drying using anhydrous Magnesium sulfate, the solvent
was evaporated in vacuo. The residue was purified with a silica gel
column to give a white solid compound based on pentaerythritol with a
constructional formula C61H123NO5, the yield is 70%.

(0.282 g, 0.316 mmol) was added under a nitrogen atmosphere to a solution
of 3-bromopropyltriethoxysilane (0.516 g, 1.264 mmol) in dry DMF (25 mL),
and the mixture was stirred for 5 days. The solvent was evaporated in
vacuo and the residue was purified by a silica gel column to afford a
colorless viscous oil based on pentaerythritol with a constructional
formula C70H144NO8Si+, the yield is 41%.

[0200] A method for preparing a hybrid lipid compound based on
pentaerythritol with a constructional formula
C80H156N4O21Si3 is as follows:

[0201] Step 1: To the solution of compound with a constructional formula

##STR00154##

(0.50 g, 0.73 mmol) and succinic anhydride (0.438 g, 4.38 mmol) in
dichloromethane (25 mL) was added DMAP (0.089 g, 0.73 mmol) and triethyl
amine (0.293 g, 2.92 mmol). The reaction mixture was heated to
30quadrature and the resultant mixture stirred at this temperature for
4 days. Then reaction solution was then concentrated under vacuum and the
residue was purified by column chromatography to give a white solid
compound based on pentaerythritol with a constructional formula
C53H93NO15, the yield is 75%.

[0204] Step 2: To the solution of compound with a constructional formula

##STR00156##

(0.30 g, 0.305 mmol) in the dichloromethane solution (20 mL) was added
DDC (0.075 g, 0.366 mmol). After 15 min of stirring,
3-aminopropyltriethoxysilane (0.308 g, 1.38 mmol) was added to the
solution and the mixture was stirred for 1 d at room temperature. Then
the solution was concentrated under vacuum and the residue was purified
with a silica gel column to give the hybrid lipid based on
pentaerythritol (colorless oil), the yield is 53%.

[0207] Dihexadecyl amine 31 (6 mmol) and succinic anhydride 32 (12 mmol)
were added to dry THF (60 mL) and dissolved upon heating. The solution
was stirred for 26 h at room temperature. The solvent was evaporated in
vacuo and the crude product was dissolved in dichloromethane (50 mL). The
solution was then washed in turn with 10% aqueous hydrochloric acid and
saturated aqueous sodium chloride. After drying using anhydrous Magnesium
sulfate, the solvent was evaporated in vacuo. The crude product was
purified with a silica gel column to give a compound 33 with a
constructional formula

[0209] To the solution of the compound 33 (2 mmol) and a compound 34 (4
mmol) with a constructional formula

##STR00159##

in DMF (40 mL) was added DCC (4 mmol) and DMAP (1 mmol) at room
temperature. The reaction mixture was warmed to 55quadrature and
stirred at this temperature for 16 hours. The solution was concentrated
under vacuum and the residue was purified with a silica gel column to
give compound 35 (C48H85NO6) with a constructional formula

##STR00160##

wherein R1 is C16 alkyl, R2 is C16 alkyl, a is 2,
R61 is -Ph, R71 is --H, the yield is 43%.

[0211] To the solution of a compound 35 (4 mmol) with a constructional
formula

##STR00161##

and a compound 411 (16 mmol) with a constructional formula

##STR00162##

in dichloromethane (40 mL) was added DMAP (2 mmol) and triethyl amine (20
mmol). The reaction mixture was stirred at 35quadrature for 26 hours.
The solution was concentrated under vacuum and the residue was purified
with a silica gel column to give a compound 36 (C52H89NO9)
with a constructional formula

[0213] In a 250 mL reactor, the compound 36 (1.75 g, 2 mmol) was dissolved
In a mixed reaction solvent of methanol and tetrahydrofuran with the
volume ratio of 1:3, palladium hydroxide/carbon (0.87 g) was added,
hydrogen was access to reach the pressure of 1.0-1.2 MPa, and the above
mixture was vigorously stirred at 50quadrature for 48 h. The solution
was concentrated under vacuum and the residue was purified with a silica
gel column to give a compound 37 (C45H85NO9) with a
constructional formula

and the mixture was stirred at 30quadrature for 48 hours. Then, the
solution was concentrated under vacuum and the residue was purified with
a silica gel column to give a compound 39
(C57H94N4O8) with a constructional formula

##STR00167##

wherein R1 is C16 alkyl, R2 is C16 alkyl, a is 2,
X1 is -Ph, Y1 is --H, the yield is 43.2%.

[0217] Under nitrogen atmosphere, to the solution of the compound 39 (1
mmol) in dichloromethane (40 mL) was added a compound III (2.5 mmol) with
a constructional formula

##STR00168##

and dibutyltin laurate (0.4 mmol), the mixture was stirred at
55quadrature for 48 hours, then the solution was concentrated under
vacuum and the residue was purified with a silica gel column to obtain
the hybrid lipid compound based on pentaerythritol
(C77H136N6O16Si2) with a constructional formula

##STR00169##

wherein R1 and R2 are C16 alkyl chains, a is 2, X1
and Y1 are --H, R311 is the group consisting of
--CONH(CH2)3Si(X)3. X is ethoxy, the yield is 50.2%.

[0219] To the solution of the compound 39 (1 mmol) and a compound 411 (6
mmol) with a constructional formula

##STR00170##

in dichloromethane (40 mL) was added DMAP (1 mmol) and triethylamine. The
reaction mixture was stirred at 35quadrature for 48 hours. The solution
was concentrated under vacuum and the residue was purified with a silica
gel column to give a compound 40 (C65H102N4O14) with
a constructional formula

##STR00171##

wherein R1 and R2 are C16 alkyl chains, a is 2, X1
and Y1 are H, R91 is the group consisting of
--CO(CH2)2COOH, the yield is 80%.

[0221] To the solution of the compound 40 (0.5 mmol) in dichloromethane
(20 mL) was added DCC (1.2 mmol) and a compound 131 (1.5 mmol) with a
constructional formula

##STR00172##

and the mixture was stirred at 30quadrature for 30 hours. Then the
solution was concentrated under vacuum and the residue was purified with
a silica gel column to give a hybrid lipid compound based on
pentaerythritol (C83H144N6O18Si2) with a
constructional formula

##STR00173##

wherein R1 and R2 are C16 alkyl chains, a is 2, X1
and Y1 are H, R321 is
--CO(CH2)2CONH(CH2)3Si(X)3, in which X is
ethoxy, the yield is 20%.

[0223] In a round 20 mL round bottom flask, 4 mg of hybrid lipid prepared
in embodiment 30 was dissolved in 5 mL of CHCl3, which was then
removed by a nitrogen stream to form a thin film layer on the wall of
vial. The film was then dried under vacuum at 35quadrature. Then,
certain volume of ultrapure water was added to the vial to reach the
final concentration of μmol/L. The mixture was ultrasonicated with a
probe-type sonicator for 5 min to obtain a solution with certain
turbidity. The resultant solution was incubated at room temperature for
12 h before measurements. Particle size of cerasome prepared in this
embodiment was detected by DLS instrument is about 156 nm, which showing
narrow particle size distribution, polydispersity index of 0.197, well
consistent with the result observed by scanning electron microscopy.
Particle size distribution is shown in FIG. 8, and scanning electron
microscopy is shown in FIG. 9.

Example 32

[0224] Cerasome solution prepared in the embodiment 31 was diluted to a
concentration of 250 μM, upon irradiation with UV light of 365 nm for
different time, the UV/Vis is absorption spectra was detected. The result
showed an obvious decrease in the absorption intensity of azobenzene unit
at about 360 nm and a concurrent increase in the peak at 450 nm. It was
an evident that trans-to-cis isomerization of azobenzene unit had
occurred. UV-visible absorption spectrum is shown in FIG. 10.

Example 33

[0225] To the solution of a compound 35 (1 mmol) with a constructional
formula

##STR00174##

in DMF (40 mL) was added a compound 141 (2 mmol) with a constructional
formula

##STR00175##

and the mixture was completely dissolved by heating. Then DCC (2 mmol)
and DMAP (1 mmol) were in turn added, the resultant mixture was heated at
55quadrature for 20 hours, and later the solution was concentrated
under vacuum and the residue was purified by a silica gel column to give
a compound 151 (C79H133NO9) with a constructional formula

##STR00176##

wherein R1 and R2 are C16 alkyl chains, a is 2, R61
is -Ph, R71 is --H, the yield is 80%.

[0227] In a 250 mL reactor, the compound 151 (2.48 g, 2 mmol) was
dissolved in a mixed reaction solvent of methanol and tetrahydrofuran
with the volume ratio of 1:3, palladium hydroxide/carbon (1.24 g) was
added, hydrogen was access to reach the pressure of 1.0-1.2 MPa, and the
above mixture was vigorously stirred at 50quadrature for 48 h. The
solution was concentrated under vacuum and the residue was purified by a
silica gel column to give a compound 161 (C72H129NO9) with
a constructional formula

[0229] Under nitrogen atmosphere, to the solution of the compound 161 (1
mmol) in dichloromethane (40 mL) was added a compound III (2.5 mmol) with
a constructional formula

##STR00178##

and dibutyltin laurate (0.4 mmol), the mixture was stirred at
55quadrature for 48 hours, then the solution was concentrated under
vacuum and the residue was purified with a silica gel column to obtain
the hybrid lipid compound based on pentaerythritol
(C92H171N3O17Si2) with a constructional formula

##STR00179##

wherein R311 is the group consisting of
--CONH(CH2)3Si(X)3, in which X is ethoxy, R1 and
R2 are C16 alkyl chains, a is 2, the yield is 53.2%.

[0231] To the solution of the compound 161 (1 mmol) and a compound 411 (6
mmol) with a constructional formula

##STR00180##

in dichloromethane (40 mL) was added DMAP (1 mmol) and triethylamine (6
mmol). The reaction mixture was stirred at 35quadrature for 48 hours.
Later the solution was concentrated under vacuum and the residue was
purified with a silica gel column to give a compound 171
(C86H137NO15) with a constructional formula

[0233] To the solution of the compound 171 (1 mmol) in dichloromethane (30
mL) was added DCC (2 mmol) and a compound 131 (2.2 mmol) with a
constructional formula

##STR00182##

and the mixture was stirred at 30quadrature for 30 hours. Then the
solution was concentrated under vacuum and the residue was purified with
a silica gel column to give a hybrid lipid compound based on
pentaerythritol (C98H179N3O19Si2) with a
constructional formula

##STR00183##

wherein R321 is the group consisting of
--CO(CH2)2CONH(CH2)3Si(X)3, X is ethoxy, the
yield is 20%.

[0235] In a 20 mL round bottom flask, 4 mg of the hybrid lipid compound
prepared in embodiment 37 was dissolved in 5 mL of CHCl3, which was
then removed by a nitrogen stream to form a thin film layer on the wall
of vial. The film was then dried under vacuum at 35quadrature. Then,
certain volume of ultrapure water was added to the vial to reach the
final concentration of 1 mmol/L. The mixture was ultrasonicated with a
probe-type sonicator for 10 min to obtain a solution with certain
turbidity. The resultant solution was incubated at room temperature for
12 h before measurements. Transmittance electron microscopy is shown in
FIG. 11.

Example 39

[0236] Add surfactant Triton X-100 (TX-100) into cerasomes prepared from
the hybrid lipid in embodiment 38 and test size changes of cerasomes,
comparing size changes of conventional liposomes made from phospholipids
(DSPC) which were used as control under the same conditions to examine
the stability of the cerasome. When 30 times amount of TX-100 solution
were added, sizes of cerasomes derived from the hybrid lipid of the
present invention remained unchanged, while particle sizes of traditional
liposomes from the DSPC decreased to zero in the presence of 5 times
amount of TX-100, which indicating vesicles structure have been
destroyed, so that it provides a strong evidence that liposomes derived
from hybrid lipid of the present invention show higher stability than the
conventional liposomes. Stability evaluated result of cerasomes is shown
in FIG. 12.

Example 40

[0237] Dissolve a compound 37 (1 mmol) with a constructional formula

##STR00184##

in dichloromethane (40 mL), then added DCC (1.2 mmol) and a compound 41
(1.5 mmol) with a constructional formula

##STR00185##

the mixture was stirred at 30quadrature for 48 hours. Then, the
solution was concentrated under vacuum and the residue was purified with
a silica gel column to get a compound 42
(C89H114N6O8) with a constructional formula

##STR00186##

wherein R1 and R2 are the same and are both C16 alkyl
chains, a is 2, X2 is --H, the yield is 63.0%.

and dibutyltin laurate (0.4 mmol), the mixture was stirred at
55quadrature for 48 hours. Then the solution was concentrated under
vacuum and the residue was purified with a silica gel column to obtain
the hybrid lipid based on pentaerythritol
(C109H156N8O16Si2) with a constructional formula

##STR00188##

wherein R1 and R2 are the same and are both C16 alkyl
chains, a is 2, X2 is H, R311 is
--CONH(CH2)3Si(X)3. X is ethoxy, the yield is 54.5%.

[0241] Dissolve the mixture of the compound 42 (1 mmol) and a compound 411
(6 mmol) with a constructional formula

##STR00189##

in dichloromethane (40 mL), then add DMAP (1 mmol) and triethylamine (6
mmol). The reaction mixture was stirred at 35 μl for 60 hours and was
then concentrated under vacuum, the residue was purified with a silica
gel column to get a compound 44 (C97H122N6O14) with a
constructional formula

##STR00190##

wherein R1 and R2 are the same and are both C16 alkyl
chains, a is 2, X2 is H, R91 is --CO(CH2)2COOH. The
yield is 85%.

the mixture was stirred at 30quadrature for 48 hours and was then
concentrated under vacuum, the residue was purified with a silica gel
column to get a hybrid lipid compound based on pentaerythritol
(C115H164N8O18Si2) with a constructional formula

##STR00192##

wherein R321 is --CO(CH2)2CONH(CH2)3Si(X)3,
X is ethoxy, a is 2, R1 and R2 are the same and are both
C16 alkyl chains, X2 is H, the yield is 30.3%.

[0245] Dissolve the compound 43 (1 mmol) in DMF (30 mL), then add a
compound 46 (10 mmol) having the formula of MY3, the mixture was
refluxed at 160quadrature for 24 hours and was then concentrated under
vacuum, the residue was purified with a silica gel column to get a hybrid
lipid compound based on pentaerythritol
(C109H154N8O16Si2Mn) with a constructional
formula

##STR00193##

wherein M is the metal ion Manganese (Mn), a is 2, R1 and R2
are the same and are both C16 alkyl chains, X2 is H, R311
is --CONH(CH2)3Si(X)3, X is ethoxy, the yield is 85.0%,
Y3 is --Cl.

[0247] Dissolve the compound 45 (1 mmol) in chloroform (30 mL), then add a
compound 46 (12 mmol) having the formula of MY3, the mixture was
refluxed at 70quadrature for 48 hours and was then concentrated under
vacuum, the residue was purified with a silica gel column to get a hybrid
lipid compound based on pentaerythritol
(C115H162N8O18Si2Zn) with a constructional
formula

##STR00194##

wherein M is the Zinc metal ion (Zn), a is 2, R1 and R2 are the
same and are both C16 alkyl chains, X2 is H, R321 is
--CO(CH2)2CONH(CH2)3Si(X)3, X is ethoxy, the
yield is 90.0%, Y3 is --Cl.

[0249] In a 20 mL round bottom flask, 4 mg of hybrid lipid prepared in
embodiment 43 was dissolved in 5 mL CHCl3, which was then evaporated
under vacuum to form a thin film layer on the wall of vial. The film was
later dried under vacuum at 35quadrature to remove CHCl3. Then,
certain volume of ultrapure water was added to the flask to make the film
reach the final concentration of 1 mmol/L and was following
ultrasonicated with a probe-type sonicator for 10 min to obtain a
solution with certain turbidity. The solution was incubated at room
temperature for 12 h to form the corresponding cerasomes. The particle
size of cerasomes prepared in this embodiment was detected by DLS
instrument, and the result shows that the particle size is about 125 nm
and with narrow particle size distribution, polydispersity index is
0.210, which is well consistent with the result observed by transmittance
electron microscopy. Particle size distribution is shown in FIG. 13, and
transmittance electron microscopy is shown in FIG. 14.

Example 47

[0250] Hybrid lipid compound 42 prepared in embodiment 43 was dissolved in
chloroform to obtain solution with the concentration of 30 uM, UV-visible
spectrophotometer was used to test its absorption spectra, the result is
shown in FIG. 15. Cerasomes prepared in embodiment 46 was diluted to
obtain solution with the concentration of 25 uM, UV-visible
spectrophotometer was used to test its absorption spectra, the result is
also shown in FIG. 15. The results show cerasomes prepared from hybrid
lipid compound still have characteristic absorption peak of the original
functional groups of porphyrin.

Example 48

[0251] Add surfactant Triton X-100 (TX-100) into cerasomes prepared in
embodiment 46 and test size changes of cerasomes, comparing size changes
of conventional liposomes made from phospholipids (DSPC) which were used
as control under the same conditions to examine the stability of the
cerasomes. When 35 times amount of TX-100 solution were added, sizes of
cerasomes derived from the hybrid lipid of the present invention remained
unchanged, while particle sizes of traditional liposomes from the DSPC
was almost decreased to zero in the presence of 5 times amount of TX-100,
which indicating vesicles structure have been destroyed, so that it
provides a strong evidence that cerasomes derived from hybrid lipid
compound of the present invention show higher stability than the
conventional liposomes. Stability evaluated result of cerasomes is shown
in FIG. 16.

Example 49

[0252] Dissolve the mixture of the compound 33 (2 mmol) and a compound 47
(4 mmol) with a constructional formula

##STR00195##

in DMF (40 mL), then add DCC (4 mmol) and DMAP (1 mmol). The reaction
mixture was warmed to 55quadrature and stirred at this temperature for
16 hours. The solution was then concentrated under vacuum to remove the
solvent, and the residue was purified with a silica gel column to get a
compound 48 (C48H85NO6) with a constructional formula

##STR00196##

Wherein a is 2, R1 and R2 are the same and are both C16
alkyl chains, X1 is H, the yield is 43%.

[0254] Under nitrogen atmosphere, dissolve the compound of 48 (1 mmol) in
dichloromethane (40 mL), then add a compound 111 (1.25 mmol) with a
constructional formula

##STR00197##

and dibutyltin laurate (0.4 mmol), the mixture was stirred at
55quadrature for 48 hours and was then concentrated under vacuum to
remove the solvent, and the residue was purified with a silica gel column
to obtain the hybrid lipid compound based on pentaerythritol
(C58H106N2O10Si) with a constructional formula

##STR00198##

wherein R1 and R2 are O16 alkyl chains, X1 is H,
R311 is the group consisting of --CONH(CH2)3Si(X)3. X
is ethoxy, the yield is 52.3%.

[0256] Dissolve the mixture of the compound 48 (4 mmol) and a compound 411
(16 mmol) with a constructional formula

##STR00199##

in dichloromethane (40 mL), then add DMAP (2 mmol) and triethylamine (20
mmol). The reaction mixture was stirred at 35 μl for 26 hours and was
then concentrated under vacuum to remove the solvent, and the residue was
purified with a silica gel column to get a compound 49
(C52H89NO9) with a constructional formula

##STR00200##

wherein a is 2, R1 and R2 are the same and are both C16
alkyl chains, X1 is H, the yield is 86%.

the mixture was stirred at 30quadrature for 30 hours and then was
concentrated under vacuum to remove the solvent, and the residue was
purified with a silica gel column to get a hybrid lipid compound based on
pentaerythritol (C61H110N2O11Si) with a
constructional formula

##STR00202##

wherein a is 2, R1 and R2 are the same and are both C16
alkyl chains, X1 is H, R321 is
--CO(CH2)2CONH(CH2)3Si(X)3, X is ethoxy, the
yield is 20%.

[0260] In a 250 mL reactor, the compound 49 (1.75 g, 2 mmol) was dissolved
in a mixed reaction solvent of methanol and tetrahydrofuran with the
volume ratio of 1:3, palladium hydroxide/carbon (0.87 g) was then added,
hydrogen was accessed to reach the pressure of 1.0-1.2 MPa, and the above
mixture was vigorously stirred at 50quadrature for 48 h and then was
concentrated under vacuum to remove the solvent, and the residue was
purified with a silica gel column to get a compound 37
(C45H85NO9) with a constructional formula

##STR00203##

wherein a is 2, Wand R2 are the same and are both C16 alkyl
chains, the yield is 52%.

the mixture was stirred at 30quadrature for 30 hours and then was
concentrated under vacuum to remove the solvent, and the residue was
purified with a silica gel column to get a hybrid lipid compound 50 based
on pentaerythritol (C54H106N2O11Si) with a
constructional formula

##STR00205##

wherein a is 2, R1 and R2 are the same and are both C16
alkyl chains, X is ethoxy, the yield is 35%.

[0264] Dissolve the mixture of the compound 50 (4 mmol) and a compound 411
(16 mmol) with a constructional formula

##STR00206##

in 40 mL dichloromethane, then add DMAP (2 mmol) and triethylamine (20
mmol). The reaction mixture was stirred at 35quadrature for 26 hours
and then was concentrated under vacuum to remove the solvent, and the
residue was purified with a silica gel column to get a hybrid lipid
compound (C62H114N2O17Si) with a constructional
formula

##STR00207##

wherein a is 2, R1 and R2 are the same and are both O16
alkyl chains, R91 is --CO(CH2)2COOH; R81 is
--CO(CH2)2CONH(CH2)3Si(X)3 and X is ethoxy. The
yield is 56%.

[0266] 4 mg of hybrid lipid compound prepared in embodiment 52 and 4 mg of
hybrid lipid compound prepared in embodiment 55 was separately put in a
20 mL round bottom flask and dissolved in 5 mL CHCl3, which was then
evaporated under vacuum to form a thin film layer on the wall of vial.
The film was later dried under vacuum at 35quadrature to remove
CHCl3. Then, certain volume of ultrapure water was added to the
flask to make the film reach the final concentration of 1 mmol/L and was
following ultrasonicated with a probe-type sonicator for 5 min to obtain
a solution with certain turbidity. The solution was incubated at room
temperature for 12 h to form the corresponding cerasomes. Transmittance
electron microscopy image of cerasome prepared in embodiment 52 is shown
in FIG. 17, and transmittance electron microscopy image of cerasome
prepared in embodiment 55 is shown in FIG. 18.